The following search terms were used: [ADHD], [prevalence], and [substance use disorder]. RStudio® was used for meta-analysis methods. (3) Results: In total, 31 studies were included. We estimate the prevalence of ADHD among SUD patients at 21%.(1) Background: Attention deficit hyperactivity disorder (ADHD) is characterized by a persistent pattern of age-inappropriate levels of inattention and/or hyperactivity/impulsivity that results in functional impairment at work, education, or hobbies and affects family life, social contacts, and self-confidence. ADHD is a comorbid condition associated with a prognosis of severe substance use disorder (SUD) and the early onset of such. The aim of this meta-analysis was to obtain the best estimate of the prevalence of ADHD in SUD populations. (2) Methods: A literature research was conducted using PUBMED Addiction has a huge impact in healthcare systems worldwide. One out of nine hospitalizations in the United States of America are made by patients with substance use disorder (SUD). Unfortunately, numbers have been increasing in recent years . FurtherThe course of SUD is strongly influenced by social environment and existing comorbidities—both somatic and psychiatric. ADHD is a common comorbidity in SUD patients  with a mPatients with ADHD are more likely to develop SUDs  at a youCurrent data indicate an ADHD prevalence of 21.5% in SUD populations . HoweverObjectives: The aim of this meta-analysis is to obtain an estimate of ADHD prevalence among adult SUD patients and SUD subpopulations for different substances, which could lead to a better understanding of the correlation between these two different psychiatric diseases, thus allowing the potential necessity of implementing screening tools for ADHD in SUD and vice versa to be studied.® and Web of Science® databases took place using the search terms [ADHD], [prevalence], and [substance use disorder]. The time period for inclusion was from 1970 to 2022. Reference lists of obtained articles were also considered. The search was conducted from 11 May 2022 to 7 July 2022.The structure of the meta-analysis was based on the preferred reporting items for systematic reviews and meta-analyses (PRISMA) 2020 guideline . LiteratThe following inclusion criteria were used (1) a publication of the research paper in a peer-reviewed journal, (2) the formal diagnosis of SUD according to DSM  or ICD , (3) theFor an overview of study inclusion and exclusion, see The extracted variables from each study were sample size, gender distribution, the mean age of the participants, the prevalence of ADHD among the population, and the main substance of abuse. For the purpose of this meta-analysis, we only extracted subpopulations of opioid-, cocaine-, and alcohol users. Studies with other substances as the main substance or with missing information on a main substance were declared to be various types of substance abuse. If sub-populations were specified within a study, we tried to take them into account in the analysis. Data were extracted and checked from each study by one and the same researcher (N.G.).Q and I2 statistics. Conventions were followed by the interpretation of I2: values of 0.25, 0.50, and 0.75 correspond to low, moderate, and high between-trial heterogeneities [The meta-analytic procedure was realized using R-software library package metafor [version 2.0-0] . A randoeneities . The pubWe conducted the same methods on the three SUD subpopulations: cocaine, opioids, and alcohol.n = 2357), seven studies with cocaine (n = 2974), and seven studies with alcohol (n = 2143) as the main substance of abuse were included. For a list of included studies, see We screened 1691 records and included 31 studies with a total participant size of 12,524. Three studies with opioids . A moderator analysis was conducted for age, suggesting that age has only a slight influence on heterogeneity, Q (df = 25) = 20.2909, p = 0.7314. For the Forest plot of the effect sizes and 95% confidence intervals, see z = −1.69, p = 0.30) suggest the absence of a publication bias . Significant heterogeneity was present . For Forest and Funnel plots, see For the subpopulation of cocaine users, we calculated an ADHD prevalence of 19%  with significant heterogeneity . For Forest and Funnel plots, see For the subpopulation of opioid users, we calculated ADHD prevalence of 18%  with significant heterogeneity . For Forest and Funnel plots, see For the subpopulation of alcoholics, we calculated ADHD prevalence of 25%  with significant heterogeneity   for sympn among them. For accuracy reasons, we excluded 46 studies only using self-reported questionnaires for confirmation of the diagnosis of ADHD.Limitations: This meta-analysis suggests that the available data of ADHD in adulthood among SUD populations is very heterogeneous; hence, the current results should be interpreted very cautiously. Furthermore, we were not able to conduct the moderator analysis with the moderator age on the three subpopulations because of the small In today’s psychiatric clinical practice, ADHD in adulthood remains a highly underrated condition, especially when focusing on people suffering from SUD. This meta-analysis shows that every fifth patient suffering from SUD could be diagnosed with a comorbid ADHD if evaluated precisely for research purposes. In order to improve mental health care for this population, new concepts for diagnosis and treatment in daily psychiatric practice in in- and outpatient care must urgently be developed. If diagnosed earlier with ADHD, it is probable that the severity of the course of SUD could be attenuated or even the occurrence itself could be prevented. However, the important question of whether people suffering from ADHD are particularly more susceptible to develop SUD to certain substances unfortunately remains unanswered. Hence, future research efforts should attempt to investigate the prevalence of ADHD among SUD populations for specific substances or substance groups more intensely to address diagnostic and therapeutic means more individually in the future.


Globally, the prevalence of attention deficit hyperactivity disorder (ADHD) is increasing. The treatment for ADHD is multifaceted and requires long-term care and support. Pharmacists are capable of assisting patients and their caretakers in achieving desired outcomes. This work discusses and summarizes pharmacists’ roles in ADHD care and their associated outcomes. Overall, pharmacists are positioned to educate on ADHD, optimize medications in a collaborative practice model, manage and monitor side effects, and provide remote and virtual pharmaceutical care. Pharmacists could directly contribute to ensuring medication safety and increasing awareness regarding the optimal use of ADHD medications. Patients with ADHD can benefit from pharmacist involvement in a variety of ways, including, but not limited to, initial screening and referral, the provision of clinical consultation and feedback, and the improvement of self-management and self-awareness of the illness. Pharmacists also play a significant role in therapeutic decision making regarding the initiation, intensification, and monitoring of ADHD treatment to ensure its effectiveness and quality of life improvement. Lastly, pharmacists could help identify more cost-effective treatment approaches for ADHD patients based on the clinical scenario that is encountered. Over the last few decades, there has been an exponential increase in the overall prevalence of mental disorders . GloballPatients with attention deficit hyperactivity disorder (ADHD) may experience a variety of adverse outcomes, and they are more likely to have children with ADHD due to the genetic components of the condition . There iADHD has a chronic impact on patients’ social and functional abilities and their risk of developing other comorbidities . Adults Because of their more frequent interactions with patients, pharmacists seem to be among the first healthcare professionals to encounter ADHD patients in their practice, particularly in community settings . PharmacThe goal of ADHD treatment is to enhance the patient’s functioning, learning, and ADHD symptoms . The trePsychoeducation, a therapeutic ADHD-focused parent-training program that provides information, support, and coping skills to the patient and their family, is recommended as the first-line intervention, particularly in children under five years . In a raFurthermore, cognitive behavioral therapy (CBT) is a behavioral therapy that recognizes and targets specific maladaptive cognitions and behaviors that cause psychological distress and dysfunction . PsychoeNeurofeedback, often known as “NF”, involves measuring an individual’s brain waves and giving them a feedback signal to educate them on how to exercise self-control over their brain activities . A randoDietary modification for ADHD is divided into elimination and supplementation diets. The elimination diet excludes artificial food coloring, additives, sugar, and artificial sweeteners, and the few-foods diet (FFD) relies on a small number of food items  for a definite period . The eviOn the other hand, a supplementation diet involves the addition of amino acids, essential fatty acids, vitamins, and minerals. In a study that included 47 newly ADHD-diagnosed children and investigated the impact of a 5-week dietary modification program, the findings showed that dietary modifications, including hypoallergenic foods, a wide range of vegetables, and reduced carbohydrate and protein intake, were associated with improvement in ADHD symptoms . DespiteOverall, with quality education and training related to dietary supplements, pharmacists could have a crucial role in supporting appropriate and safe dietary supplement use among diverse groups of patients, including those with neuropsychiatric conditions . HoweverADHD pharmacotherapy includes several therapeutic choices, including stimulants such as methylphenidate and amphetamine, noradrenergic drugs such as atomoxetine, and alpha-2A-adrenergic agonists such as guanfacine and clonidine . For chiIn general, clinical pharmacy gains more attention and characterizes pharmacists’ main role in providing services such as medication reconciliation, therapeutic education, and taking part in multidisciplinary teams to help optimize pharmacotherapeutic decisions for patients with neuropsychiatric disorders . ConcernPrevious research has highlighted several knowledge gaps regarding ADHD and its treatment and suggested that further education to raise awareness of ADHD is needed . With suEducational interventions may come in a spectrum of forms and use varied platforms . In a stA study carried out among Toronto pharmacists observed that the majority of pharmacists were not very familiar with ADHD medications and management, indicating that many pharmacists still need further support to equip them with the essential knowledge and skills . To builThe optimization of medicines assists patients in terms of medication adherence, long-term management, multiple morbidities, and polypharmacy . ExampleNon-adherence to prescribed medications among ADHD patients is a multifactorial issue, and one of the reasons is that patients are not fully aware of the optimal way to manage the disease and the prescribed pharmacotherapy . It is pPharmacists can collaborate with psychiatrists to provide independent follow-up in ADHD clinics. Integrating clinical pharmacists into an ADHD specialty clinic improves patients’ adherence to ADHD treatment . InitialFurthermore, the experience of a pharmacist-led interprofessional ADHD clinic in a large integrated healthcare system found that the clinic has successfully shown improvements in terms of cost and efficiency of operations, and a large portion of patients reported positive outcomes in terms of fulfilling the ADHD clinic service, achieving a stabilization point, and not being re-referred to the same facility within 1 year . PatientSome individuals may develop unfavorable adverse effects, necessitating administration, dose, or medicine modification. Pharmacists may find the ADHD rating scale useful in closely monitoring the effects of medicine on the core symptoms of inattention, hyperactivity, and impulsivity . The sidFrom the pharmacists’ point of view, a Canadian study highlighted that about 67% of pharmacists believe that psychostimulants are the most common cause of initial insomnia. Interestingly, community pharmacists had significantly higher knowledge of ADHD compared to hospital pharmacists, which might be caused by the lower number of ADHD patients encountered by hospital pharmacists . AccordiA pharmacist must recognize how stimulants influence appetite and growth in children with ADHD. Children using stimulants should have their height and weight assessed regularly, such as semi-annually . Both stThe use of technology in healthcare, including pharmacy practice, is well established and covers many medical specialties . The feaAccording to the EAGG guidelines, pharmacists are required to educate families about the importance of reporting any symptoms related to the heart, such as palpitations, shortness of breath, or chest discomfort, as soon as possible. Furthermore, the guidelines recommend that all appointments involving initial assessments of children with ADHD should continue, but they should be conducted remotely using videoconferencing or telephone, in line with the telepsychiatry guidelines . Table 3Telepsychiatry refers to using remote technology to assess and intervene while providing mental health services ,60,61. TNon-adherence to medication usually occurs in late adolescence and is associated with various adverse health outcomes, such as higher chances of injuries and emergency department visits . A telepIn a retrospective evaluation of introducing the collaborative model of pharmacists’ involvement in providing regular counseling and psychological services as a part of an interprofessional team with psychiatrists, the findings showed improvements in adherence to clinical monitoring and compliance with the medication-taking policy . This inADHD has a serious and negative impact on a child or adolescent’s health-related quality of life (HRQOL). It has a moderate impact on the physical domain while having a severe impact on the psychosocial domains, which include emotional, social, and school interactions . There iIt is well established that patients with ADHD tend to have higher direct medical costs compared to individuals without ADHD. According to one German analysis, the main drivers of this increased cost are inpatient care, psychiatrists and psychotherapists, and comorbidities such as anxiety, substance use disorders, and obesity . In thisIn collaboration with other healthcare providers, pharmacists are ultimately responsible for providing comprehensive ADHD education and support, selecting the most appropriate treatment agent, optimizing the pharmacotherapeutic regimen, and developing a monitoring plan. Pharmacists’ involvement in ADHD care is associated with better chances of achieving clinical outcomes, improving quality of life, and increasing the chances of a cost-effective treatment plan. Though they are capable of performing these responsibilities, it is imperative that they stay current on updates to the ADHD clinical standards and recommendations.


Attention-Deficit Hyperactivity Disorder (ADHD) is a complex and heterogeneous neurodevelopmental condition for which curative treatments are lacking. Whilst pharmacological treatments are generally effective and safe, there is considerable inter-individual variability among patients regarding treatment response, required dose, and tolerability. Many of the non-pharmacological treatments, which are preferred to drug-treatment by some patients, either lack efficacy for core symptoms or are associated with small effect sizes. No evidence-based decision tools are currently available to allocate pharmacological or psychosocial treatments based on the patient's clinical, environmental, cognitive, genetic, or biological characteristics. We systematically reviewed potential biomarkers that may help in diagnosing ADHD and/or stratifying ADHD into more homogeneous subgroups and/or predict clinical course, treatment response, and long-term outcome across the lifespan. Most work involved exploratory studies with cognitive, actigraphic and EEG diagnostic markers to predict ADHD, along with relatively few studies exploring markers to subtype ADHD and predict response to treatment. There is a critical need for multisite prospective carefully designed experimentally controlled or observational studies to identify biomarkers that index inter-individual variability and/or predict treatment response. Only in the last decades have these questions been addressed by applying systematic measurement of mostly physical, neurocognitive, and behavioral symptoms. The subsequent development of laboratory and imaging techniques to analyze and visualize the interior of the body and the brain have further revolutionized clinical medicine. Today, we are at the transition to an additional level of medical insight known as precision, stratification, or personalized medicine (PM). This perspective paper aims to describe the per se individualized. In a more narrow sense, PM aims to offer evidence-based tailored assessment and treatment to each patient and thereby is an advancing field of healthcare that is informed by each person's unique clinical, genetic/genomic, biomarker, and environmental information , course or treatment response; it can be a physical, chemical, biologic, genetic, cognitive, psychological or environmental measure see  Drucker. UnfortuDeveloping and validating biomarkers requires high-quality study designs. Biomarker discovery may start with retrospective analysis of randomized controlled trial (RCT) datasets for moderator effects. However, most such retrospective analyses are underpowered and/or lack a hypothesis; which is why findings need to be confirmed in prospective designs. The field of oncology has generated advanced designs for testing biomarkers , amphetamines, lisdexamphetamine, atomoxetine (ATX), guanfacine] are associated with moderate to large effect sizes across multiple trials in children older than 6; however, not every individual with ADHD responds well to every medication  or non randomized studies exploring cognitive, physiological (EEG/ERP), MRI, genetic and clinical measures that may serve as biomarkers to predict diagnosis, stratify ADHD into more homogenous subgroups and/or predict response to treatment and/or predict course  markers such as theta and beta oscillations at rest reflecting arousal, alertness, orienting and activation  to predict a diagnosis of ADHD in case-control designs see . TBR wasLongitudinal work has identified consistent neurophysiological patterns related to differential outcomes. Children with ADHD persisting into adulthood show increased beta and reduced frontal theta EEG at rest  often in combination with actigraphy or movement assessments to index the inattention, impulsivity and hyperactivity symptom domain to develop cognitive diagnostic markers predicting ADHD . Other mPsychological factors such as compliance, suggestibility, motivation, coping strategies, and cognitive capacities are all important predictors of treatment success and should be considered when taking a whole person approach to PM  showed that, for families from the lowest socioeconomic strata, who required welfare support, only Combined Treatment of medication and psychosocial intervention yielded meaningful benefits with respect to the outcome of teacher-reported social skills  and hypothesis-driven (for hypothesis testing). Firstly, big data science, such as exploitation of large case-registry data bases, will be useful for exploratory analyses and hypothesis generation with regard to clinical and family-genetic markers of course and outcome. Infrastructure such as the United Kingdom Biobank also offers unprecedented opportunities for exploratory analyses capitalizing on access to genetic, brain imaging and other biological data and soon also to information on ADHD symptoms scores  framework  across sites for biomarker assessment, including achieving standards for test-retest reliability, across-site reproducibility and accuracy. Feasibility will also be an issue, as, for example, MRI biomarkers may be scientifically relevant as probes into the neural underpinnings of ADHD but less implementable into clinical practice. Appropriate statistical techniques for predictive modeling that may exploit the potential of advances machine learning approaches should be used . GP is supported by São Paulo Research Foundation  and National Council for Scientific and Technological Development . LR is supported by the National Council for Scientific and Technological Development . Medice was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.JB has been in the past 3 years a consultant to/member of advisory board of / and/or speaker for Shire, Roche, Medice, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, royalties. LR has received grant or research support from, served as a consultant to, and served on the speakers' bureau of Eli Lilly and Co., Janssen, Medice, Novartis and Shire. The ADHD and Juvenile Bipolar Disorder Outpatient Programs chaired by LR have received unrestricted educational and research support from the following pharmaceutical companies: Eli Lilly and Co., Janssen, and Novartis. LR has received authorship royalties from Oxford Press and ArtMed and travel grants from Shire to take part in the 2018 APA annual meeting and from Novartis to take part of the 2016 AACAP annual meeting. Barbara Franke has received educational speaking fees from Medice and Shire. SB discloses that he has in the last 5 years acted as an author, consultant or lecturer for Shire, Medice, Roche, Eli Lilly, Prima Psychiatry, GLGroup, System Analytic, Ability Partner, Kompetento, Expo Medica, Clarion Healthcare, and Prophase. He receives royalties for text books and diagnostic tools from Huber/Hogrefe, Kohlhammer and UTB. DB serves as an unpaid scientific advisor for an EU-funded neurofeedback trial unrelated to the present work. TB served in an advisory or consultancy role for Actelion, Hexal Pharma, Lilly, Lundbeck, Medice, Neurim Pharmaceuticals, Novartis, Shire. He received conference support or speaker's fee by Lilly, Medice, Novartis and Shire. He has been involved in clinical trials conducted by Shire & Viforpharma. He received royalties from Hogrefe, Kohlhammer, CIP Medien, Oxford University Press. The present work is unrelated to the above grants and relationships. DC served in an advisory or consultancy role for Medice, Novartis, Shire/Takeda. He received conference support or speaker's fee by Medice, Servier and Shire/Takeda. He has been involved in clinical trials conducted by Shire. He received royalties from Oxford University Press. The present work is unrelated to the above grants and relationships. In the past year, SF received income, potential income, travel expenses continuing education support and/or research support from Tris, Otsuka, Arbor, Ironshore, Shire, Akili, Enzymotec, Sunovion, Supernus and Genomind. With his institution, he has US patent US20130217707 A1 for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received support from: Shire, Ironshore, Neurovance, Alcobra, Rhodes, CogCubed, KemPharm, Enzymotec, Akili, Neurolifesciences, Lundbeck/Takeda, Otsuka, McNeil, Janssen, Novartis, Pfizer and Eli Lilly. He also receives royalties from books published by Guilford Press: Straight Talk about Your Child's Mental Health, Oxford University Press: Schizophrenia: The Facts and Elsevier: ADHD: Non-Pharmacologic Interventions. He is principal investigator of www.adhdinadults.com. Guilherme V. Polanczyk has been in the past 3 years a consultant, member of advisory board, and/or speaker for Shire/Takeda and Medice. He received travel expenses for continuing education support from Shire/Takeda and royalties from Editora Manole. In the past three years, Jeffrey Newcorn is/has been an advisor and/or consultant for Adlon Therapeutics, Akili Interactive, Alcobra, Arbor, Cingulate Therapeutics, Enzymotec, KemPharm, Lundbeck/Takeda, Medice, NLS, Rhodes, Shire, and Supernus. He was a DSMB member for Pfizer and Sunovion, and received research funds from Enzymotec, Otsuka, Shire and Supernus. He also has received speaker fees from Shire for disease-state presentations, and served as a consultant for the US National Football League. BV has served as consultant to Medice and Teva Pharm. Markus Gleitz is an employee of Medice Arzneimittel Pütter GmbH & Co. KG. MS received research support from Supernus, Shire, and Akili Interactive labs and in the past year has served in a advisory or consultancy capacity to Genomind, NLS, Shire/Takeda, Supernus, and Sunovian. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer KAJ declared a shared affiliation with the author DC to the handling editor at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


IL17D, IL22RA2, IL20RB, IL10RA, IL10RB, TSLP and TYK2) are involved in the JAK/STAT pathway which promotes tumor progression. The upregulation of IL22RA1 in tumors was correlated with immune cell infiltration level. Higher expression of IL22RA2, IL20RB, IL10RA, IL10RB, TSLP, TYK2, STAT1 and STAT3 was associated with decreased overall survival rate in patients. IL22RA1 mutation was observed more in uterine cancer and melanoma compared with the other cancer types. Deactivation of IL22RA1 induced a lot of changes in gene expression. IL22RA1 mutants had upregulated DNA damage/repair genes in uterine cancer, whereas downregulated genes in the FoxO signaling pathway. In melanoma, mutation of IL22RA1 can upregulate the HIF signaling pathway but downregulate metabolic pathways. Our study suggests that IL22RA1/JAK/STAT signaling can be an important target for cancer treatment.Cytokines and cytokine receptors are important mediators in immunity and cancer development. Interleukin 22 (IL22) is one of the most important cytokines which has protumor effect. Given that common and specific roles of cytokines/receptors in multiple cancers, we conducted a pan-cancer study to investigate the role of IL22RA1 in cancer using The Cancer Genome Atlas (TCGA) database. Notably, we found IL22RA1 transcript was upregulated in 11 cancer types compared with their corresponding control. The mRNA expression level of IL22RA1 was highest in the pancreas among tumor tissues. The higher expression of IL22RA1 was associated with worse overall survival rate in patients. A total of 30 IL22RA1-correlated genes (e.g.  Cancer has been a leading cause of death in the world since 2020 . Among types of cancer treatment, immunotherapy is becoming one of the most effective strategies against cancer, as it can strengthen the power of the immune system . NeverthIL22RA1 is an important heterodimeric receptor for interleukin 22 (IL22) which is involved in chronic inflammation and tumor development. IL22RA1 is expressed on cell membrane of nonimmune cells including epithelial cells from different organs or hepatocytes . ThroughIL22 promotes tumorigenicity in pancreatic ductal adenocarcinoma through IL22RA1/STAT3 signaling . IL22 siOur study used the TCGA databases to conduct a pan-cancer analysis of IL22RA1 for the first time. Here the expression and mutation status of IL22RA1 as well as the associated genes and immune cells were covered.http://timer.comp-genomics.org/) (RNA seq data from TCGA database were performed using TIMER 2.0 (cs.org/)  includinhttps://xenabrowser.net).The overall survival rate of patients with high or low expression of target genes was performed using the TCGA/TARGET/GTEx RNA-Seq dataset based on UCSC Xena (http://www.ndexbio.org/). Pathway analysis of these 31 genes was performed by The Database for Annotation, Visualization and Integrated Discovery (DAVID) v6.8. The transcripts level for IL22RA1-related genes were analyzed using the TCGA/TARGET/GTEx RNA-Seq dataset through UCSC Xena.A total of 30 genes and proteins have been found related with IL22RA1 by NCI/Nature (https://www.mutarget.com) (The effect of mutation status of IL22RA1 on gene expression in cancer was explored using TCGA database by muTarget (get.com)  and UCSCProteins were extracted from uterine cancer tissues and adjacent normal control tissues from dogs at Animal Hospital of Northeast Agricultural University. This study was approved by Ethical Committee of Northeast Agricultural University. Primary antibodies used were 1:1000 anti-IL22RA1  and 1:7500 anti-β-actin . Then membranes were incubated with secondary horseradish peroxidase-HRP conjugated antibodies . The protein bands were visualized using Champ Gel 6000 image system . Image-Pro Plus 6.0 software  was used to analyze the density for each band. Results are presented as the ratio of the intensity of the IL22RA1 band to the intensity of the β-actin band.p < 0.05. Differentially expressed genes were based on |log2 fold change| > 0.5 and adjusted p < 0.05. GraphPad Prism Version 8.0  was used for graph generation. All data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test.Data are expressed as means ± standard deviation (SD). Differences were considered statistically significant at .Compared with normal tissues, the transcript level of IL22RA1 in tumor tissues was upregulated in a total of 11 cancers including bladder urothelial carcinoma (BLCA), cervical and endocervical cancer (CESC), cholangiocarcinoma (CHOL), esophageal carcinoma (ESCA), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), lung squamous cell carcinoma (LUSC), stomach adenocarcinoma (STAD), and uterine corpus endometrial carcinoma (UCEC) . Notably, higher expression of IL22RA1 was associated with poor survival in patients .In humans, IL22RA1 was highly expressed in the pancreas, rectum, and small intestine . NotablySTAT5B, STAT5A, IL13, CSF2, IL10RA, IL20RB, TYK2, IL9, IL23A, IL10RB, IL22RA1, IFNL2, IL22, IFNL1, IL24, IL19, IFNL3, IL17D, IL20, IFNA13, IL22RA2, IL6, IL4, PTPN11, IL2, IL10, JAK1, STAT1, STAT3, IL5, and TSLP) were related with IL22RA1 based on https://www.ndexbio.org/iquery/. Protein interaction network also showed a relationship between these 31 proteins . We further explored the correlation of IL22RA1 and the related 30 genes in each cancer (from TIMER2). IL22RA1 was positively correlated with STAT1, STAT3, JAK1, PTPN11, IFNA13, IL24, but negatively correlated with IL10 in specific cancers  .A total of 30 genes . It was positively correlated with CD4+ Th2 cells in BLCA (rho = 0.24), as well as CD4+ T cells and regulatory T cells (Tregs) in CESC (rho = 0.25), CD4+ effector memory T cells in KIRC (rho = 0.30), CD4+ T cells in LUAD (rho = 0.26). In addition to T cells, IL22RA1 was positively correlated with myeloid dendritic cells (rho = 0.23) and macrophage M0 in BLCA (rho = 0.20) as well as macrophage/monocyte in KIRP (rho = 0.43) and KIRC (rho = 0.39) .As both genomic and transcriptomic changes are important signatures for cancer development, and gene mutation can alter the expression of certain genes. We further wanted to investigate whether mutation of IL22RA1 can change gene expression, and what are the functions of the affected genes. The non-silent mutation among diverse cancer types is mainly distributed in uterine cancer (>25%) and melanoma (> 20%) SLX4, RAD51, EME1, FANCA, BRCA1], homologous recombination ), and one carbon pool by folate , whereas downregulated 59 genes involving alcoholic liver disease  and the FoxO signaling pathway  . Gene encoding CCND1 was also upregulated in IL22RA1 mutant compared with wild-type. CCND1 is dysregulated in many cancers, indicating mutation of IL22RA1 contributes to cancer development .Based on mutant (n = 19) versus wild-type (n = 507) in uterine cancer, IL22RA1 mutation upregulated 156 genes, which involved in DNA repair (fanconi anemia pathway [ PRKAG2) . Gene enSERPINE1 and PFKP by IL22RA1 mutation were involved in the HIF-1 signaling pathway. However, genes in biosynthesis of unsaturated fatty acids , butanoate metabolism , and other metabolic pathways , as well as ECM-receptor interaction  were downregulated by IL22RA1 mutation .In melanoma, a total of 14 genes were upregulated, whereas 77 genes were downregulated when comparing IL22RA1 mutated and wild-type patient cohorts. Upregulated p < 0.01; IL22RA1 transcript was higher in UCEC tissues   pathway. The JAK/STAT signaling pathway directly regulates the crosstalk between transmembrane receptors to the nucleus . ThroughConsistent with IL22RA1, higher expression of IL10RB, IL10RA and IL20RB in tumor tissues was associated with worse survival in patients. IL22R1 is expressed only by nonhematopoietic cells, whereas IL10RB (IL10R2) is ubiquitously expressed by all tissues and cells . OverexpOverexpressed thymic stromal lymphopoietin (TSLP) and tyrosine kinase 2 (TYK2) was also associated with worse survival through pan-cancer analysis. TSLP is an epithelial-cell–derived cytokine that contributing to inflammation driven by Th2 cells . TSLP alGene alterations lead to cancer initiation and driving progression . Silent In melanoma, IL22RA1 mutation upregulated the expression of genes involved in the hypoxia-inducible factor-1alpha (HIF-1α) signaling pathway, whereas the metabolic pathways including biosynthesis of unsaturated fatty acids and butanoate metabolism were downregulated. Hypoxia, as a major feature of solid tumors, activates HIF-1α that enhances tumor growth and leads to melanoma progression by regulating the expression of genes involved in angiogenesis, metabolism, cell proliferation, and metastasis .In conclusion, IL22RA1 together with genes involved in the JAK/STAT pathway contribute to cancer development. Immune cell infiltration level in tumor tissues is associated with IL22RA1 expression. IL22RA1 mutation in uterine cancer and melanoma induced overexpression of genes that are favorable in tumor progression. These findings indicate that IL22RA1 may act as a contributor to tumorigenesis with a direct and indirect role in the process. However, more detailed mechanism in specific cancer still needs to be investigated.The original contributions presented in the study are included in the article/The animal study was reviewed and approved by Ethical Committee of Northeast Agricultural University. Written informed consent was obtained from the owners for the participation of their animals in this study.Conceptualization, GY; Data analysis and writing, SZ and GY; All authors have read and agreed to the published version of the manuscript.This work was supported by the National Natural Science Foundation of China Grant (Grant No. 32002351) and International Postdoctoral Exchange Fellowship Program 2019 of China Postdoctoral Council .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To conduct the first systematic review and meta-analysis assessing whether attention-deficit/hyperactivity disorder (ADHD) is associated with disorders of the eye, and/or altered measures of visual function.Based on a pre-registered protocol (PROSPERO: CRD42021256352), we searched PubMed, Web of Knowledge/Science, Ovid Medline, Embase and APA PsycINFO up to 16th November 2021, with no language/type of document restrictions. We included observational studies reporting at least one measure of vision in people of any age meeting DSM/ICD criteria for ADHD and in people without ADHD; or the prevalence of ADHD in people with and without vision disorders. Study quality was assessed with the Appraisal tool for Cross-Sectional Studies (AXIS). Random effects meta-analyses were used for data synthesis.g = 0.63 ) and variability  of the accommodative response; and increased self-reported vision problems  in people with ADHD compared to those without ADHD (with no significant heterogeneity). We also found meta-analytic evidence of no differences between people with and without ADHD on retinal nerve fiber layer thickness  and refractive error  (with no significant heterogeneity).We included 42 studies in the narrative synthesis and 35 studies in the meta-analyses . We found meta-analytic evidence of increased risk of astigmatism , hyperopia and hypermetropia , strabismus , unspecified vision problems  and reduced near point of convergence ; increased lag (Hedge’s ADHD is associated with some self-reported and objectively ascertained functional vision problems, but not with structural alterations of the eye. Further studies should clarify the causal relationship, if any, between ADHD and problems of vision.PROSPERO registration: CRD42021256352. Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder affecting 5% of children and 3% of adults and characterized by developmentally inappropriate inattention and/or hyperactivity/impulsiveness –3. ADHD Considering that vision problems, including vision loss, blurred vision and strabismus, are influenced by environmental biological factors  investigate if the prevalence of ADHD differed in people with and without vision problem and, vice versa, if the prevalence of vision problems/conditions differed in people with and without ADHD; and (b) investigate differences in objective measures of vision  between people with and without ADHD.This systematic review and meta-analysis followed the 2020 PRISMA  guidelines . The PRIWe systematically searched Pubmed, Web of Knowledge/Science, Ovid Medline, Embase and APA PsycInfo until 16th November 2021, with no language/type of document limits. The search strategy/syntax included keywords associated with (a) ADHD and (b) vision  original, observational studies ; (2) including people of any age meeting DSM III, III-R, IV (TR), 5 or ICD 9–10 diagnostic criteria for ADHD; and (3) comparing at least one measure of vision in people with vs. those without ADHD. Moreover, we also included studies reporting the prevalence of ADHD in people with and without any disorders of vision.Titles and abstracts of studies retrieved from the searches were screened independently by two authors (AB and JP) to identify those that potentially met inclusion criteria; disagreements were resolved through discussion. The full text of each article marked as eligible for inclusion was assessed for final inclusion. Data were extracted from eligible studies using standardized forms by two authors (AB and JP). Extracted information included: study design, sample characteristics , clinical characteristics , outcome measures . Data not available from publications were systematically requested from corresponding, first or senior authors via e-mail. Publications for which data were initially not available and were received by the authors are indicated in Table For studies that reported mean and SD of any outcome measure within the scope of the review, in people with and without ADHD, the standardized mean difference (Hedge’s g) and its variance were calculated . The natR 4.1.0 , z = 0.2112, p = 0.8328; Table Sg = −0.3604, SE = 0.2563, 95% CI = , t = −1.4065, p = 0.2323; Table Sg = 0.0579, SE = 0.2698, 95% CI = , t = 0.2147, p = 0.8405; Table Sg = −0.2219, SE = 0.1721, 95% CI = , t = −1.2895, p = 0.2181; Table Sg = 0.1164, SE = 0.1568, 95% CI = , z = 0.7423, p = 0.4579; Table Sg = −0.1917, SE = 0.1103, 95% CI = , z = −1.7386, p = 0.0821; Table SThe meta-analyses showed no significant differences between people with and without ADHD on axial length (Hedge’s p changed from 0.0821 to 0.5660). Trim and fill analyses could not be performed for the meta-analyses on axial length and macular volume, because only two studies were included in such meta-analyses.Estimation from trim and fill analyses showed that no study was missing due to publication bias in the meta-analyses conducted on GCLT Fig. Sb, c, intincreased near point of convergence in ADHD. Karaca et al. , t = 0.4358, p = 0.6855; Table SQ = 20.7980, p = 0.0003) and publication bias was not detected   Fig. S. Estimat3) Fig. Sb, c.Among the studies that could not be included in the meta-analysis (for which we did not have available data to compute effect sizes), Fabian et al.  found nog = 0.6326, SE = 0.0875, 95% CI = , t = 7.2322, p < 0.0001; Table SQ = 16.3265, p = 0.1767) but publication bias was detected   both when conducting the trim and fill analysis on all effect sizes except the largest effect sizes for , t = 1.5653, p = 0.1175) with no significant heterogeneity . No additional studies were included for narrative synthesis only.Four studies analyzing self-reported vision problems in people with and without ADHD were included in the meta-analyses , 69, 74 1) Fig. S. Trim anizes for , and wheizes for . When inizes for  which hoWe conducted a systematic review and meta-analysis to investigate the association between ADHD and disorders or problems of vision. We found evidence of an association between ADHD and reduced color discrimination and contrast sensitivity, atypical accommodative response and convergence. No association between ADHD and visual acuity or refractive error was detected, and we did not find evidence of an association between ADHD and anatomic ocular measures . However, we found an association between ADHD and astigmatism, hyperopia and hypermetropia, and strabismus (but not myopia), but we did not detect a higher prevalence of ADHD in patients diagnosed with problems of vision.Our findings reaffirm the importance of physical and visual examinations in evaluating patients with ADHD, as suggested by multiple practice guidelines –77. VariThis is further confounded by the close and intertwined relationship between perception and higher-level cognitive functions, and an incomplete understanding of the pathophysiology of ADHD. So far, the neurocognitive symptoms that define ADHD are largely conceived of as arising from structural and molecular abnormalities in the brain . The braWhile we did not detect a relationship between ADHD and anatomic measures, ADHD was associated with increased risk of disorders caused by atypical corneal curvature and eye shape, and problems in controlling eye muscles . Although the development of specific components of the retina may not be affected in ADHD, other major structures of the eye may develop atypically in ADHD, increasing the risk of problems of vision.In contrast to the anatomic measures, we detected an association between ADHD and diminished contrast sensitivity and impaired color discrimination, in which the retina is potentially implicated. Impairments in these functions have also been reported in neuropsychiatric disorders in which catecholaminergic transmission is affected , color vision and contrast sensitivity, and visual acuity. These results, although statistically significant, need to be considered cautiously. Heterogeneity is probably due to differences in the methodology used for obtaining anatomic measures, different paradigms used to investigate color vision and contrast sensitivity, and heterogeneity in the ascertainment and diagnosis of study participants. Lastly, publication bias was detected for the meta-analyses of studies on color vision and contrast sensitivity, and for differences in self-reported vision problems. The trim and fill analyses for color vision and contrast discrimination found that, after correcting for publication biases, their pooled effect sizes were not statistically significant. Considering that measures of vision are less variable than measures of ADHD symptoms, they may not be as sensitive in capturing the heterogeneity of ADHD compared with diagnostic measures. Moreover, future research should investigate if specific disorders of vision are specifically associated with ADHD or also with other neurodevelopmental conditions, e.g., autism. Lastly, because most of the studies in the meta-analysis were sampled from clinically referred populations, the generalizability of our results is limited to such samples due to Berkson’s bias  and other methodological issues, as previously discussed.In conclusion, we found meta-analytic evidence of a significant association of ADHD with self-reported and objectively ascertained functional vision problems, but not with structural or anatomic alterations. Further studies are needed to investigate what type of causal relationships exist between ADHD and specific problems of vision, and how much one can explain the others.Supplemental Materials


The aim of this study was to determine the relationship between the altitude of residence and the low birth weight (LBW) of the children of pregnant Peruvian women using a nationally representative database. An analysis of individual-level data from the last 13 years (from 2009 to 2021) of the Demographic and Family Health Survey was performed. The outcome variable was LBW, defined as birth weight less than 2500 g, while the independent variable was the altitude of residence in meters above sea level (masl). To estimate the association between the two variables, the crude and adjusted generalized linear model of the Poisson family with a log link was used along with crude and adjusted prevalence ratios, which were estimated with their respective 95% confidence interval. A total of 151,873 women aged 15–49 years were included between 2009 and 2021. The pooled proportion of LBW was 7.0%. As the main finding, the children of mothers residing at an altitude from 2500 to 3499 masl and ≥3500 masl had a higher probability of LBW. It was found that the children of mothers residing at an altitude above 2500 masl were more likely to have LBW. Our results will help to strengthen the cultural practice of maternal health care and increase its coverage in women residing in high-altitude regions. According to the World Health Organization (WHO), low birth weight (LBW) is a public health indicator that encompasses maternal health and nutritional problems, deficiencies in health care during pregnancy, and socioeconomic conditions . LBW is The biomedical literature suggests that factors such as fetal sex and maternal and socioeconomic characteristics can influence the presentation of LBW in a newborn ,11,12,13In Peru, high-altitude regions (Andes region) are characterized by their location in rural areas and at an altitude exceeding 2500 masl ,27,28,29http://iinei.inei.gob.pe/microdatos/, accessed on 20 November 2022). The 2009 ENDES was used because the survey has been conducted annually since that year. Briefly, the ENDES is a nationally representative survey that uses a complex sampling design and collects information on sociodemographic and health indicators of women of childbearing age and their children under 5 years of age. The sampling methodology used in the ENDES is provided in detail in the technical reports of the survey [The present study used individual-level data from the Demographic and Family Health Survey (ENDES—acronym in Spanish) conducted between 2009 and 2021  ,44,45,46Women selected for the individual questionnaire for women of childbearing age were included in this study. The individual questionnaire collected information on demographic and social characteristics, reproductive history, contraceptive use, maternal and child health, fertility, and domestic violence, among the main topics ,44,45,46The study sample included women of childbearing age between 15 and 49 years who had had a child within the last five years at the time of the survey. Likewise, women with a residence time of 5 years or more were included. Women who did not reside in the altitude cluster at the time of pregnancy were excluded.The outcome variable of this study was LBW coded as “1” if the mother reported that the child was born weighing less than 2500 g and “0” otherwise. This classification was based on the definition given by the WHO [The exposure variable was the altitude of the cluster where the dwelling was located. In the ENDES, specifically since 2015, the measurement of the altitude was given in masl using an application to obtain georeferenced data  through a global positioning system measured at one meter from the front door of the respondent’s home ,50,51,52Covariates were selected based on previous studies and data available in the ENDES ,33,54. TA combined database of the 13 years (from 2009 to 2021) of the ENDES was constructed and used for analysis. We used Stata version 17.0 (StataCorp) for data management and analysis. Prior to any statistical analysis, the data were weighed using the sampling weight, PSU, and strata to consider the representativeness and sampling design of the ENDES by using the ‘svy’ command. To specify the sample design, a strata and cluster identifier was created for each year of the ENDES, and the sample weight was divided by 1,000,000.p-value of <0.05 was considered statistically significant.Initially, a descriptive analysis was performed to report the characteristics of the participants, including the frequency of LBW, the frequency of women by their altitude of residence, and the covariates of interest using absolute and relative frequencies for each year which were pooled. Next, the crude and adjusted generalized linear model of the Poisson family with a log link was used to evaluate the association between LBW and the altitude of residence. The association results are expressed as prevalence ratios (PR) and their 95% confidence intervals (CI). The possible problem of multicollinearity was evaluated by performing a variance inflation factor test which found no correlation between the independent variable and covariates. A http://iinei.inei.gob.pe/microdatos/ (accessed on 20 November 2022) were used. The process of downloading and using the ENDES databases is described in the study by Hernández-Vásquez and Chacón-Torrico [Approval from a research ethics committee was not sought for this retrospective study because only anonymized secondary data that are in the public domain and available at -Torrico . ENDES pA total of 151,873 women aged 15–49 years were included between 2009 and 2021. Of the total participants included, 51.3% of the children were male, and 47.6% of the mothers belonged to the 25–34 age group. In addition, 26.3% of the mothers were nulliparous, and most of the mothers belonged to the middle (22.1%) and poor (21.8%) wealth quintiles and resided in an urban area (76.4%). On the other hand, the highest proportions of LBW were observed in the years 2010 (8.0%), 2013 (7.9%), and 2015 (7.5%), while the lowest proportions were found in the years 2014 (6.2%), 2019 (6.2%), and 2021 (6.5%). Further details of the characteristics of the population included according to the year of the survey are shown in Overall, the pooled proportion of LBW between 2009 and 2021 was 7.0%. Likewise, the highest prevalence of LBW was observed in female children (7.4%) whose mothers belonged to the 15–24 age group (7.8%) and who were their first child (7.6%). Additionally, mothers residing between 3500 and 3499 masl (9.0%), belonging to the poorest wealth quintile (9.3%), and in a rural area (8.5%) had the highest proportion of children with LBW .On average, we found that 71.6% of the mothers resided at an altitude lower than 1500 masl, followed by 14.0%, 7.9%, and 6.4% of the mothers residing at an altitude from 2500 to 3499 masl, ≥3500 masl, and from 1500 to 2499 masl; respectively . RegardiIn the crude model, the LBW was associated with an altitude of residence from 2500 to 3499 masl and ≥3500 masl. Likewise, the same pattern was found in both the adjusted and the crude models. Specifically, model 1, which was adjusted for the mother’s age, child’s sex, wealth quintile, nulliparity, and area of residence, found that the children of mothers residing at an altitude between 2500 and 3499 masl  and ≥3500 masl  had a higher probability of having LBW, while in model 2, when adjusted for all variables in model 1 and the survey year, the same pattern was identified, with the children of mothers residing at residence altitudes of 2500–3499 masl  and ≥3500 masl  demonstrating a higher probability of presenting LBW .The sample weights and sample design of ENDES were included for all the estimates.Model 1: Model with the age group of the mother, sex of the child, nulliparity, wealth index, and area of residence.Model 2: Model with the age group of the mother, sex of the child, nulliparity, wealth index, area of residence, and year of the survey.Our study sought to determine the association between the altitude of residence in Peruvian mothers and the presence of LBW in their children by performing an analysis comprising 13 years of a nationally representative survey. We found the pooled proportion of LBW to be 7% in the study period. As the main finding, we observed that after adjusting for potential confounders, mothers residing at an altitude of 2500–3499 masl and ≥3500 masl had a higher probability of having a child with LBW compared to those residing at an altitude lower than 2500 masl. It should be noted that the temporality of this association was based on the assessment of LBW in the last child under five years of age.We found that 7% of newborns were found to have LBW in the study period, with LBW ranging from 6.2% in 2014 and 2019 to 8.0% in 2010. This finding is lower than that reported in studies conducted in high-altitude regions of the United States (11.8%)  and NepaThe identified association between the altitude of maternal residence and LBW has previously been reported in the biomedical literature ,23,33,54Our results could have an impact on clinical practice and public health. In clinical practice, the association between the altitude of residence and LBW observed in our study could allow health personnel to better follow and comply with prenatal check-ups of pregnant Peruvian women residing at a high altitude (>2500 masl). On the other hand, maternal health care that seeks to reduce negative perinatal outcomes in rural or high-altitude regions should implement an intercultural approach since native women (Aymara or Quechua) have ancestral practices that generate a negative perception of maternal health care, resulting in a higher frequency of home births attended by midwives and lower use of formal health services . In addiOur study has limitations and strengths. First, one of the main limitations is the cross-sectional design of our study, which prevents establishing causality between the variables of interest due to a lack of temporality in their measurement. Therefore, longitudinal studies are required to determine the causality between the exposure variable  and the outcome variable (LBW). Second, as birth weight is a variable self-reported by the mother, there could be a recall bias or inaccuracy in the data since the interviewer requests the exact amount of the newborn’s weight from the last pregnancy in the last five years. Third, by using different years of the ENDES, different sample frames were obtained that could have generated differences in the characteristics of the mother and child between each year, and this may have been more notable in the 2020 and 2021 ENDES, which collected part of the information by telephone due to the COVID-19 pandemic ,46. FourIn conclusion, it was found that mothers residing at an altitude above 2500 masl were more likely to have children with LBW. In this sense, the findings of this study will allow the development of strategies that include the cultural practices of women and ensure greater coverage and control of pregnant women to reduce the prevalence and consequences of LBW throughout the life of the newborn.


Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent psychiatric disorders among school-age children and is characterized by varying degrees of inattention, hyperactivity, and impulsivity. Diagnosis, which currently relies on the DSM-V criteria, is complex. This research proposes an integrated procedure for ADHD diagnosis in children, improving the diagnostic process and scientific research on etiopathology.n = 92) between the ages of 8 and 13, based on the results of the application of different scales to parents of school-age children in Chile. The children were divided into two groups, those with an ADHD diagnosis (n = 44) and those without (n = 48) .We conducted a clinical report on ADHD diagnosis in children (The results revealed statistically significant differences between groups for scales EDAH y SDQ-Cas, Conners Comprehensive Behavior Scale, Conners Parent Scale and the criteria according to the DSM-V and its dimensions, with the exception of inattention.The findings indicate the importance of appropriate criteria and procedures to establish a diagnosis and implement effective interventions in ADHD. Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder characterized by symptoms of inattention, impulsivity, and hyperactivity , which interfere with development and impact the individual’s functional, personal, and social spheres , which cAccording to the last review by Rendering to that study, the prevalence of ADHD in Chile is 10.3% among children ages 4–18, with the highest prevalence in ages four to eleven , representing one of the highest prevalence in the world . The mosAn ADHD diagnosis mainly relies on the criteria established in the Diagnostic and Statistical Manual of the American Academy of Psychiatry (DSM) . Both thThis shows that the thresholds for classifying a child’s behavior as disproportionate will always be arbitrary to some degree; here factors such as the cultural norms of each context, an adequate knowledge of typical childhood development, and the expectations of parents and teachers all come into play. These differences led to discrepancies, which some authors have argued that the prevalence varies according to age and the number of symptoms observed by informants . MoreoveThere is no standardized approach to integrating the multiple sources of information into an ADHD diagnosis. Nor does the recent fifth edition of the DSM offer this possibility, due to a lack of empirical data that would allow for the integration of all mechanisms that figure into a diagnosis . In factVarious studies based on neuroimaging and electrophysiological measurements have supported the hypothesis of ADHD’s neurobiological origin, although its exact etiology cannot yet be confirmed. It is also essential to consider that ADHD is a pathology with a high heritability rate, estimated at up to 80% . Other sMany authors e.g.,  have proAdditionally, due to the heterogeneity of the disorder’s clinical presentation and the absence of a biomarker, professionals often resort to diagnosis by exclusion after assessing for other comorbid pathologies that present similar behavioral manifestations, as reported in the study by Following that the state of the art about ADHD limit it diagnosis to the solely clinical analysis, in Chile the disorder is diagnosed by qualified professionals  in accordance with guidelines by the Ministry of Education and Ministry of Health (Decree number 170/2010). In short, it means that the diagnosis is made through the check of the criteria that encompasses the disorder.The Chilean decree guidelines indicate that the diagnosis process follows a three steps protocol, which includes (1) the classification according to the most recent edition of diagnostic classification manuals, a (2) detection and assessing process based on criteria such Conners Test, and a (3) comprehensive diagnostic process including a diagnosis by exclusion review. To this point, it is important to note that the behavioral observation is made based on the Conners Test, which is a questionnaire that is widely disseminated on the internet and does not fulfill the international diagnostic recommendations .Habilidades para la vida”  and a single measure .n = seventy) and girls (n = twenty-two), between the ages of eight and sixteen  participated in the study. Children were recruited in Chilean public schools catering to populations with a similar socioeconomic status, belonging to three educational establishments in the city of Talca and one educational establishment in the city of Santiago (Chile). These schools were characterized to implement the Integration School Program (PIE), where children with ADHD have a previous diagnosis from a psychiatrist. The schools were selected from a database of schools participating in other research projects. The inclusion criteria for this study were: (a) a diagnosis of ADHD and (b) no history of cognitive impairment, brain trauma, neurological disease, physical disability, comorbid mental disorders , or learning disorders. For the neurotypical group, participants were matched by gender, age, and IQ scores (in the case of the ADHD group). Any children presenting symptoms that could indicate ADHD were excluded. All children had an IQ above the 75th percentile, according to the results of Raven’s Colored and Progressive Matrices  = 17.502, p < 0.05. According to the allocation criteria, 44 children were assigned to the ADHD group (Group 1) and 48 children to the neurotypical group (Group 2). No significant differences were found in most of the sociodemographic variables, except in the use of medication: χStandard instruments validated for a Spanish-speaking population were used, except for the anamnesis form and the ADHD diagnostic checklist, which the authors developed for the specific purposes of this study.1.ad hoc instrument composed of nine elements, which records information provided by the parent/guardian regarding the birth history, development, and health of the child, and sociodemographic characteristics of the family unit.Anamnesis Record: an 2.Conners Scales : the ada3.Scale for the Evaluation of Attention Deficit Hyperactivity Disorder— EDAH-, its Spanish acronym : validat4.The SDQ-Cas questionnaire : a study5.Attention deficit hyperactivity disorder diagnostic checklist: the ADHD diagnostic criteria defined in the DSM-V  and usedThis study is part of a FONDECYT–project (1181472) and obtained ethical approval by the National Agency for Research and Development (ANID) of Chile. The Research Ethics Committee of the Autonomous University of Chile also approved the study .First, an invitation was extended to each school to participate in the research. Once the school principal had provided informed consent, the project was overseen by the research team in conjunction with the directors of technical-pedagogical units, school integration programs, or other pertinent professionals. Then, the parents of the children who were potential participants were contacted to respond to the battery of instruments used to characterize the children. After this stage of evaluation, the data were screened according to inclusion and exclusion criteria, and the pertinent statistical analyses were carried out.The assumptions of normality and homogeneity of variance were verified, and all variables followed a non-normal distribution except for the EDAH and the SDQ-CAS scales.p > 0.05); linearity was checked (met when p < 0.05); and error independence was verified with the Durbin-Watson test . Since not all assumptions were satisfactory, Spearman’s bivariate correlations (ρ) were calculated. In those cases where the chi square cannot be applied, Fisher’s exact test was used. The Mann-Whitney U statistic was used in all cases except those that fulfilled the assumption of normality and homoscedasticity, in which case Student’s t statistic was used. Cohen’s d was used to calculate the effect size based on the differences.Version 26.0 of the statistical package SPSS was used for the descriptive calculations and contrasts of means. And for the estimation of statistical power and effect size, the GPower version 3.1 package was used. To compare the means between the groups, a minimum significance level of 0.05 was considered. The confidence intervals in the estimates of the parameters were 95%. Normality assumptions were verified using the Shapiro-Wilk test . Since then, ADHD has become one of the most extensively studied—yet also one of the most controversial—disorders . TherefoThe results of the application of the clinical tests in this study demonstrate the discrimination capacity of the instruments used for the evaluation and diagnosis of ADHD. One interesting finding was the results of the SDQ-Cas, consistent with prior scientific literature indicating its ability to discriminate and suggesting it may be helpful during a diagnosis as a supplementary indicator of ADHD. In turn, the analyses of the detailed results of the DSM-V criteria showed that the hyperactivity dimensions and other indicators were statistically significant. This was not the case for inattention, which suggests that this indicator is not determinant in a diagnosis of the disorder and should be considered jointly with other markers that confirm a hypothesis of ADHD.Finally, the correlational analyses revealed significant direct effects for the correlations between most of the instruments. This indicates the usefulness of combining the instruments to enhance the process of diagnosing ADHD, which, in turn, ratifies the importance of defining a diagnostic protocol.By contributing to the discussion on the evaluation and diagnosis of ADHD, this article set out to demonstrate the importance of establishing appropriate mechanisms to ensure that children receive a correct assessment and diagnosis regardless of their sociodemographic characteristics. Based on the findings herein and scientific advances in this field, there is a need for a protocol that can render professional practice more effective and standardize it for children with ADHD.Children’s families and schools are generally the first to distinguish the symptoms of ADHD, which is why most of the instruments used for a diagnosis involve an initial assessment of the child’s behavior by their teachers and parents . Also, iIn this regard, the relevance of the present study becomes apparent. The results reveal the need for an assessment alternative that allows for greater procedural objectivity and a diagnosis based on more integrated appraisals of ADHD symptoms. The new assessment process could incorporate, for example, experimental tests that can reduce the time of an ADHD diagnostic procedure and increase its accuracy . LikewisDiagnosing ADHD is a delicate task that is the subject of much debate around its etiology and, consequently, its symptoms. Therefore, it is a multifactorial disorder and needs to be addressed as such. Regarding future research, this work suggests that more investigation is needed into the changing diagnostic criteria of the main classification manuals, the evolution of how the disorder is conceptualized, and international differences in its assessment. This is crucial because one of the possible causes of overdiagnosis and underdiagnosis is the existence of ineffective instruments . MoreoveChildren with ADHD represent a heterogeneous population and vary greatly in the degrees and severity of symptoms . Follow-Considering all that has been presented herein, the implication of this study relies on both clinical and practical areas. Regarding the clinical implications, on one hand, the construction of an integrative theoretical model for ADHD, incorporating hypotheses that support the biological, genetic, environmental, cognitive, and emotional factors that compose it, will impact directly on the comprehension and the handling of the disorder, for all those health professionals who have the power of the assessment and diagnosis process. On the other hand, regarding the practical implications, a change on the conception of ADHD diagnosis and the availability of a protocol to guide the practice will have a strong impact on the daily basis of several educational professionals and, therefore, on many families who put their trust in them.The present study presents some limitations in its execution. One of the main limitations of the study is the sample size which makes it difficult to generalize the findings obtained. Our procedure consisted of collecting data for 1 year. Initially we proposed to incorporate more schools, but due to the social unrest in Chile, the end of 2018, followed by the COVID-19 outbreak, it became impossible for us. Although the results obtained are representative of the schools being evaluated, in the immediate future we hope to incorporate more schools and consider including other age ranges, given that attentional capacity varies according to developmental stages .Another limitation presented by the study is that the anamnesis form and the ADHD diagnostic checklist have not been validated for the Spanish-speaking population. For future developments, when the sample size allows, we will conduct validity and reliability studies. Specifically: validity evidence based on test content. Expert specialists will examine whether the proposed items are relevant, useful, and feasible . EvidencBecause ADHD is the most common behavioral disorder of childhood, an appropriate and sensitive evaluation of symptoms is essential . Even soFinally, the findings of this study will allow for the implementation of essential considerations in the assessment and diagnosis of children with ADHD and contribute to advancing the discussion in the scientific community.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Comité Ético Científico de la Universidad Autónoma de Chile. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.The initial idea was generated by DM and IF and developed by all authors. IF collected all the information. JL-L analyzed the data. All authors wrote the manuscript, made a substantial contribution to the design of the document and improving both its writing and structure, consented to this final version for publication, and agreed to be responsible for all aspects of the work, such as the accuracy of the data and the completeness of the investigation.


Background: This study investigates the prevalence of lower urinary tract symptoms (LUTS) in school-age children with Attention-Deficit/Hyperactivity Disorder (ADHD) based on hospital-based and population-based cohorts. Methods: The hospital-based sample comprised 42 children with ADHD and 65 without ADHD aged 6–12 years. Voiding dysfunction was assessed by the Dysfunctional Voiding Scoring System (DVSS) questionnaire. We compared the baseline data, DVSS score, and uroflowmetry between the two groups. For the population-based cohort in the national insurance database, we included 6526 children aged 6–12 years, whose claims record included the diagnosis of ADHD, and another 6526 control subjects matched by gender and age. We compared the presence of LUTS diagnosis codes between the two groups. Results: Our results showed that, for the hospital-based cohort, the mean total DVSS score and the proportion of significant LUTS in children in the ADHD group were significantly higher than in subjects in the non-ADHD group. The DVSS subscales showed that the item “I cannot wait when I have to pee” item was significantly higher in the ADHD group . For the population-based cohort, children with ADHD had a significantly higher likelihood of storage symptoms  and enuresis  compared with those of the no ADHD group. Conclusions: Children with ADHD have a higher prevalence of significant LUTS, especially storage symptoms and enuresis, than children without ADHD. The observed correlations between ADHD and LUTS provided the supporting evidence to evaluate the concomitant voiding dysfunction in children with ADHD. Attention-Deficit/Hyperactivity Disorder (ADHD) is an occurring pediatric and adolescent neurodevelopmental disorder that affects around 5–10% of school-age children . The preEmerging evidence indicates that voiding dysfunction or nocturnal enuresis are associated with ADHD in children ,11,12,13Few studies compared hospital-based and population-based cohorts directly. The strength and power of the correlation between potential confounders for disease or bothersome symptoms differed according to controls selection. A weaker or negative estimation with hospital-based controls may exist compared with population-based controls because of selection bias ,18.This study examines the prevalence of LUTS in school-age children with ADHD, investigates whether children with ADHD are more likely than their peers to have LUTS, and compares the results of the hospital- and population-based data.Between January 2013 and December 2015, we enrolled 42 children aged between 6 and 12 years with confirmed diagnoses of ADHD from the child and adolescent psychiatric clinic in a tertiary referral center in Taiwan. Another 65 children without ADHD were enrolled from pediatric clinic in the same hospital for other non-LUTS related complaints. ADHD was diagnosed according to DSM-IV criteria as the existence of disease symptoms for more than 6 months continuously and in two different environments (at home and school) without any organic causes. The validated Chinese version of the SNAP-IV was written by the parent(s) of each child ,20. ChilLUTS in children were defined based on the terminology of the International Children’s Continence Society . The assThe National Health Insurance Bureau of Taiwan (NHI) has collected records of all inpatient and outpatient medical benefit claims for nearly the entire population of Taiwan since the inception of its single-payer NHI program in 1995. The entire data collection is known as the NHIRD .This study used a dataset, the Longitudinal Health Insurance Database (LHID) 2005, collected from the NHIRD. The LHID2005 collected all the original claims data of 1,000,000 recipients enrolled in 2005, randomly sampled from the 2005 registry for recipients of the NHIRD. There are approximately 25.6 million individuals in this registry. There was no significant difference in the gender distribution between the patients in the LHID2005 and the original NHIRD , which rLUTS diagnosis codes were defined by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) as follows: Voiding symptoms contained codes of voiding difficulty (788.1), urinary retention , incomplete emptying (788.21), postvoid dribbling (788.35), weak urine stream (788.6), splitting of the urinary stream (788.61), and slowing of the urinary stream (788.62). Storage symptoms contained frequency , polyuria , incontinence , nocturia (788.43) bladder hypertonicity (596.51), nocturnal enuresis (788.36), nocturia (788.43), and urinary urgency (788.63). Subjects whose diagnoses had concurrent codes of urinary tract infection  were excluded from the sample.Concomitant anomalies or congenital disabilities were identified by ICD-9-CM codes 740–759 in all study subjects and were also included in the analysis. Then, we analyzed the presence of any of specific diagnoses of LUTS in study sample during the study period, 2013 to 2015. In the NHIRD-based sample, we included 6526 children aged 6–12 years, whose claims record included the diagnosis of ADHD  during the period. Another 6526 control subjects were randomly selected whose claims records did not contain any diagnosis of ADHD. The control subjects were matched to the ADHD patients by gender, age, and having claims records in the year of the case subject’s initial ADHD diagnosis.This institutional-based study was approved by the Research Ethics Committee of National Taiwan University Hospital. The national insurance database used in this study was deidentified; therefore, the institutional review board waived informed consent from the enrolled patients.t-test and chi-square test. Two-sided tests were used, and a p-value of less than 0.05 was statistically significant. All data in the present study were analyzed with commercial statistical software .The numerical data were described by means and standard deviations or medians and ranges. The categorical data were expressed as counts and percentages. The numerical and the categorical data were compared with the Student’s p = 0.55). There were 14 (33.3%) girls and 28 (66.6%) boys in the ADHD group; 18 girls (27.7%) and 47 (72.3%) boys in the no ADHD group (p = 0.54). The maternal age of the subjects with ADHD was significantly younger than those without ADHD . There were no significant differences between the ADHD and the no ADHD groups regarding parental age, prematurity, household income, maternal education, maternal marital status, sibling number, type of delivery, and perinatal history. The DVSS scores with subscale, flow rate, and voided volume of study subjects are shown in p = 0.042). The subscale, “I cannot wait when I have to pee,” was significantly higher in the ADHD group . In addition, the voided volume of the uroflowmetry study was significantly lower in the ADHD group . The sleep quality score of the ADHD group was worse than the no ADHD group . Although constipation (14.2% vs. 7.7%) and enuresis (26.1% vs. 18.5%) were more frequently seen in children with ADHD than those without ADHD, the differences were not statistically significant. For the hospital-based cohort in p = 0.045) than in children without ADHD. The storage, voiding symptoms, and enuresis were comparable for both groups. The baseline data of the study sample are presented in p < 0.001). In the claim records, regarding associated anomalies, children with ADHD had a higher risk of concomitant anomalies. Among them, when compared with those of the no ADHD group, children with ADHD had more musculoskeletal  and neurological  anomalies. According to p < 0.001). Additionally, children with ADHD were more likely to have LUTS diagnoses  and nocturnal enuresis .A total of 6526 children with the diagnosis of ADHD and another 6526 age- and gender-matched control subjects without ADHD diagnoses were enrolled. Demographically, p < 0.01), which showed only borderline significance in the hospital-based cohort (p = 0.06). Previous studies have indicated that voiding dysfunction and enuresis are more prevalent in children with ADHD ,10,13,15For reasons of representativeness, utilizing a population-based cohort is admitted as being more acceptable than that of a hospital-based cohort. One conceivable reason for the differences showed between the two cohorts was Berkson’s bias. The hospital-based cohort may have been easier to be admitted for exposure of interest like enuresis, and it was the severity of the disease that led to hospital visits. This would bias the results for a correlation toward the null hypothesis with the hospital-based cohort and away from the null hypothesis utilizing the population-based cohort .The exact theories to explain the associations between ADHD and voiding dysfunction remain unclear. Decreased brain stem inhibition led to failure to detect the bladder signals and lower responsiveness to a full bladder were thought to be involved in the linkage ,30. In aThe correlation between ADHD and enuresis was mentioned in previous studies ,15,16,31Our study sample comprised children aged between 6 and 12 years. The diagnosis of LUTS in the nationwide population-based sample mainly depended on the claims data of the health insurance rather than an accurate medical history reported by the parents or physical examinations and urinalysis. However, diagnoses of voiding dysfunction in the hospital-based sample were based on the validated DVSS questionnaires ,34 and uIn the hospital-based database, children with ADHD had a higher DVSS score and higher subscale, “I cannot wait when I have to pee,” and less voided volume of the uroflowmetry study. In addition, the sleep fragmentation of the ADHD group was worse than that of the no ADHD group. The institution-based sample showed that children with ADHD had a higher total DVSS score, higher probability of the subscale (cannot wait to pee), and lower voiding volume than those in the no ADHD group. The healthcare-seeking prevalence of LUTS in children with ADHD was 5.8% compared with 3.3% in those without ADHD. Meanwhile, children with ADHD had a significantly higher risk of storage symptoms and nocturnal enuresis.The strengths of the present study are as follows: First, previous studies were mostly conducted in western countries and had a cross-sectional design. Our study provides the 6-year observation of healthcare-seeking prevalence of LUTS in an Asian cohort. Second, the NHI covers over 99% of Taiwan’s 23 million population, and the NHI databases are representative of the general population. Moreover, NHIRD datasets are not designed for research purposes and can minimize selection bias. In addition, the insurance claims data inevitably included some diagnostic errors. All claimed records of the NHIRD are subject to a quality-control process that includes cross-comparison with medical chart information. In this way, some diagnostic errors in the raw claims data are rectified during the quality-control process.Our study has some limitations. First, we investigated the presence and severity of voiding at outpatient clinic by single measurements for DVSS and uroflowmetry at one time-point, which may limit the reliability of the research in the hospital-based sample. Due to invasiveness for the children, we did not collect sufficient data such as pressure flow study, bladder sonography for a greater bladder wall thickness, and post-void residual volume, so further urodynamic approaches, and outcomes with long follow up durations are warranted in the future. Second, some study subjects with the diagnosis of ADHD in the nationwide health insurance database were diagnosed by primary care physicians rather than by a comprehensive assessment by psychiatrists. Moreover, the prevalence of LUTS in the population-based sample was healthcare-seeking prevalence, which may be lower than the data of previous studies conducted by interviews. It is worth noting that a significant proportion of children with enuresis or voiding dysfunction did not seek medical treatment. Nevertheless, the healthcare-seeking LUTS is clinically significant to some degree. Lastly, ADHD is composed of three types of symptoms: attention deficit, hyperactivity, and impulsivity. It is necessary to conduct prospective studies on the prevalence of voiding dysfunction in school-age children with different ADHD symptoms. School-age children with ADHD have a higher prevalence of LUTS, especially bothersome storage symptoms and voiding dysfunction than those without ADHD. Child healthcare providers should routinely screen for LUTS or voiding dysfunction in school-age children with ADHD.


To evaluate the electroretinogram waveform in autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) using a discrete wavelet transform (DWT) approach.–2. A DWT analysis was performed using the Haar wavelet on the waveforms to examine the energy within the time windows of the a- and b-waves and the oscillatory potentials (OPs) which yielded six DWT coefficients related to these parameters. The central frequency bands were from 20–160 Hz relating to the a-wave, b-wave and OPs represented by the coefficients: a20, a40, b20, b40, op80, and op160, respectively. In addition, the b-wave amplitude and percentage energy contribution of the OPs (%OPs) in the total ERG broadband energy was evaluated.A total of 55 ASD, 15 ADHD and 156 control individuals took part in this study. Full field light-adapted electroretinograms (ERGs) were recorded using a Troland protocol, accounting for pupil size, with five flash strengths ranging from –0.12 to 1.20 log photopic cd.s.mp < 0.001) in the coefficients corresponding to energies in the b-wave  and OPs (op80 and op160) as well as the b-wave amplitude. Notable differences between the ADHD and control groups were found in the b20 and b40 coefficients. In contrast, the greatest differences between the ASD and control group were found in the op80 and op160 coefficients. The b-wave amplitude showed both ASD and ADHD significant group differences from the control participants, for flash strengths greater than 0.4 log photopic cd.s.m–2 (p < 0.001).There were significant group differences (This methodological approach may provide insights about neuronal activity in studies investigating group differences where retinal signaling may be altered through neurodevelopment or neurodegenerative conditions. However, further work will be required to determine if retinal signal analysis can offer a classification model for neurodevelopmental conditions in which there is a co-occurrence such as ASD and ADHD. Altered retinal signaling in neurodevelopmental conditions such as autism spectrum disorder (ASD) , 2020b, Autism spectrum disorder and ADHD are the main neurodevelopmental disorders diagnosed in early childhood with a global prevalence estimated at approximately 1 and 3.4%, respectively . The co-The retina has three cell types connected in a vertical signaling pathway from the photoreceptors to the bipolar cells and then to the ganglion cells. Lateral neurons modify this path at two points: horizontal cells feedback to regulate the signal between photoreceptors and bipolar cells and amacrine cells link bipolar and ganglion cells . The retThe DWT allows the energy to be determined within frequency bands at discrete time windows within the whole ERG waveform. The method was first applied to the ERG by p < 0.001) although age would not be a factor in this young population with ERG amplitudes remaining stable from ages 15 to 24 years before media opacities influence the amount of light reaching the retina (2(2), 28.1 p < 0.001].A total of 55 ASD, 15 ADHD, and 156 control individuals took part with mean age (years) ± SD of: ASD: 14.2 ± 4.9; range (6.0–27.3), ADHD: 15.8 ± 3.2; range (8.4–21.8) and control: 13.2 ± 5.0; range (3.1–26.7) Kruskal–Wallis test ]; ADHD group: 88 ± 10 [range 72–105 for N = 7 (measure available for 47% of the group)].Participants were excluded if there was a history of strabismus surgery, other syndromic or metabolic disorders, or if there was a history of brain injury. We excluded participants who had co-existing ASD and ADHD, ADD, or OCD. Cognitive abilities were measured by the age-appropriate Wechsler scales: ASD group (mean ± SD): 101 ± 20 . Only waveforms with an a-wave amplitude >1 μV were included  represents the wavelet coefficients at discrete frequencies (j) and discrete time windows (k), for the raw signal x(t) of the ERG waveform of amplitude vs. time, with ψ representing the Haar square wavelet function (The DWT function (Eq. 1) where the function .The coefficients within each time window represent the energy (μV.s) within the signal which were extracted for statistical analysis. A scalogram presents the energies within each frequency band centered on  within time windows between –20–17.5 and 0–17.5 ms (a-wave), 17.5–55 ms (b-wave), and 8.125–55 ms and 8.125–55 ms (OPs) .The DWT analysis gives results for the energy in the 20 Hz (ON-pathway) and 40 Hz (OFF-pathway) for the a- and b-wave components  as well The DWT analysis was performed in MATLAB (Mathworks Inc.). See , 2017 fovia the “mctp” function in the “nparcomp” R package with its default settings . In addition to the “mctp” adjusting p-values for multiple comparisons, a stringent p < 0.005 was adopted as a cut-off of statistical significance  at each of the five flash strengths for each of the six DWT-related dependent variables, the b-wave amplitude and %OPs. The method proposed by ificance . Confidehttps://doi.org/10.25451/flinders.17712347.v3See p > 0.09).Scalogram plots of the DWT coefficients are shown in p-values comparison between the three groups for each of the DWT coefficients and the b-wave amplitude (b_amp) and %OPs for the two main flash strengths of 1.204 and 0.602 log photopic cd.s.m–2  for the ADHD group. The respective energies (μV.s) for ADHD and controls at this flash strength were: Median (95% CI) ADHD group: b20 104.1 (96.0–112.6), b40 93.1 (87.0–101.6), op80 30.8 (28.7–35.9), and op160 17.9 (16.6–18.9). For the control group: b20 68.6 (65.6–71.4), b40 62.8 (61.0–65.6), op80 23.6 (23.1–24.2), and op160 13.6 (13.1–13.9). In contrast, for the ASD and control group differences at 1.204 log photopic cd.s.m–2 there were no significant differences for the b20 and b40 coefficients (p > 0.008) but there were significant differences (p < 0.001) for the op80 and op160 coefficients with the ASD coefficient values being: b20 65.2 (62.6–70.2), b40 55.5 (52.3–60.9), op80 20.2 (19.0–21.4), and op160 10.8 (9.9–11.7).p < 0.003) across several flash strengths but only at the highest flash strength of 1.204 log photopic cd.s.m–2 for ADHD (p < 0.001) with median (95% CI) values of: ASD 54.3 (53.7–55.2), control 57.1 (56.4–57.5), and ADHD 55.3 (53.8–55.5)%.The %OPs as a measure of the contribution of the OPs to the overall broadband ERG energy were significantly reduced for the ASD (p < 0.001) only for flash strengths from 0.398 to 1.204 log photopic cd.s.m–2 and at the maximal flash strength of 1.204 log photopic cd.s.m–2 the respective values for a20 for the ADHD and control groups were: [median (95% CI)]: 29.5 (27.2–35.3) μV.s and 22.5 (21.2–24.0) μV.s. The a40 component representing the OFF-pathway was also significantly lower (p < 0.001) for the ASD group compared to control at the 0.602 and 1.204 log photopic cd.s.m–2 flash strengths with significant group differences observed between the ADHD and control group only at the two weakest flash strengths of –0.119 and 0.398 log photopic cd.s.m–2 (p < 0.001).The a20 component representing the ON-response showed a significant increased energy for ADHD compared to the control group (p < 0.001). For example, at the 1.204 cd.s.m–2 flash strength the b-wave amplitudes (μV) [median (95% CI)] were: ASD 23.5 (21.7–25.7), control 30.4 (28.4–31.3), and ADHD 37.2 (33.3–41.1). See As previously reported, the light-adapted b-wave amplitude was reduced for ASD compared to controls , 2020b ap > 0.48) using robust percentage bend correlation method  with the main coefficients contributing to the elevated b-wave in ADHD being b20 and b40. In contrast, in keeping with the reduced op80 and op160 coefficients in ASD the %OPs were significantly lower for the ASD group compared to the control group for all flash strengths greater than 0.4 log photopic cd.s.m–2 (p ≥ 0.005) supporting the reduced contribution of the OPs to the overall b-wave amplitude in ASD.The %OPs were not significantly different between ADHD and control for flash strengths lower than 1.20 log photopic cd.s.mEvidence from mouse models also supports the clinical findings here. A recent study using the BTBR inbred mouse strain as an ASD model showed reductions in the b-wave response under dark and light adapted conditions  as well The pathophysiology of ADHD and ASD remains a conundrum. There are no biomarkers for either condition, and we know multiple genetic and environmental factors contribute to the phenotypes . We provDiscrete wavelet transform analysis has been applied to other clinical conditions. For instance, the multifocal ERG and the pattern ERG reveal a positive association with primary open angle glaucoma . In congAnalysis of the ERG waveform using wavelet functions [as well as other signal analysis techniques such as Variable Frequency Complex Demodulation (VFCDM), , or FuncThis study is the first to apply a wavelet transform approach to analyzing clinical waveforms in neurodevelopmental conditions using the ERG. The method allows an objective description of the ON- and OFF- pathways as well as the contribution of the OPs to the overall ERG signal. A combination of time domain (b-wave amplitude) and time-frequency domain parameters  may assist with developing classification models of ADHD and ASD in the future, as well as providing a simple method to extract information on the underlying contributions of the ON- and OFF- pathways without the need for modeling luminance-response functions across several flash strengths . We spechttps://doi.org/10.25451/flinders.17712347.v3.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: This study was reviewed and approved by the Flinders University Human Research Ethics Committee and the South East Scotland Research Ethics Committee in the United Kingdom. Written informed consent to participate in this study for those under 16 years of age was provided by the participants’ legal guardian/next of kin.PC wrote the first draft and collected ERG recordings with IL and DT. FM-R conducted the statistical analysis. DS contributed to the main discussion and clinical assessments. PC and MG performed the DWT analysis. All authors contributed equally to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.