Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with an unclear etiology. Systemic inflammation and immune dysregulation may play a role in the pathogenesis of ADHD. Morphology-derived parameters such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR), have been proposed as peripheral biomarkers of the immune-inflammatory process in various diseases. However, studies examining their role in ADHD remain inconclusive.A systematic review and a meta-analysis were conducted to evaluate the association between NLR, MLR, PLR and ADHD. Relevant articles were identified, screened, and assessed for quality according to PRISMA guidelines. Moreover, a qualitative and quantitative analyses were performed.The review contained eight eligible studies, five of which were included in the meta-analysis. The meta-analysis showed that ADHD patients had higher NLR and PLR values compared to health controls. No significant difference in MLR value was observed between the two groups. Analysis in relation to ADHD subtypes showed no significant differences in inflammatory markers in any of the included studies as well. The influence of medical treatment on these ratios could not be adequately assessed due to limited data.ADHD patients exhibit higher NLR and PLR than healthy controls, which may indicate the potential immune-inflammatory involvement in this disorder. Further studies on inflammatory markers and ADHD, especially those considering the impact of treatment and clinical symptoms, are essential to comprehensively understand this association. Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterized by persistent patterns of inattention, hyperactivity, and impulsivity . The disIn recent years, there has been a growing interest in exploring the role of systemic inflammation and immune dysregulation in the pathogenesis of ADHD , 5. InflAlterations in various peripheral blood cell ratios, such as neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), and monocyte to lymphocyte ratio (MLR), have been shown to serve as potential biomarkers of immune-inflammatory processes or poor prognoses in various diseases, such as cancers, cerebrovascular, cardiovascular, or autoimmune diseases –16. In rTo date, several studies have investigated the link between NLR, PLR, MLR, and ADHD, but the findings have been inconsistent. Some studies have reported elevated ratios among individuals with ADHD, suggesting a potential role of inflammation in the pathophysiology of the disorder , 22. HowTherefore, the aim of this study was to conduct a systematic review and meta-analysis to evaluate the association between immune-inflammatory markers such as NLR, PLR, MLR, and ADHD. Specifically, we planned to: (1) compare NLR, MLR, PLR levels between ADHD patients and healthy controls; (2) assess the effects of psychostimulant treatment on NLR, MLR, PLR in ADHD patients; (3) evaluate the association of NLR, MLR, PLR levels with ADHD subtypes; (4) evaluate the association of NLR, MLR, PLR levels with ADHD symptoms and their severity. To our best knowledge, no systematic review on this topic has been conducted to date.We hypothesized that NLR, MLR and PLR levels differ significantly between ADHD patients and healthy controls, and that psychostimulant treatment affects these markers in ADHD subjects. We also hypothesized that NLR, MLR and PLR level differ in various subtypes of ADHD and are related to symptoms and severity of the disease. This systematic review and meta-analysis provide a comprehensive insight into the relationship between NLR, MLR, PLR and ADHD.This systematic review was conducted according to the PRISMA statement  .A literature search in April 2023 included the contents of Pubmed, Scopus, and Web of Science electronic databases without any filters. Additionally, clinicaltrialregistry.gov was searched. The following search strategy was used: (“neutrophil-to-lymphocyte ratio” OR “NLR” OR “neutrophil to lymphocyte ratio” OR “neutrophil/lymphocyte ratio” OR “neutrophil-lymphocyte ratio” OR “neutrophil lymphocyte ratio” OR “platelet-to-lymphocyte ratio” OR “PLR” OR “platelet to lymphocyte ratio” OR “platelet/lymphocyte ratio” OR “platelet-lymphocyte ratio” OR “platelet lymphocyte ratio” OR “monocyte-to-lymphocyte ratio” OR “MLR” OR “monocyte to lymphocyte ratio” OR “monocyte/lymphocyte ratio” OR “monocyte-lymphocyte ratio” OR “monocyte lymphocyte ratio”) AND (“ADHD” OR “Attention Deficit Hyperactivity Disorder”). In addition, references from selected articles were screened to confirm potentially related studies.The following criteria were a condition for the inclusion of the studies in this systematic review: (1) observational study design ; (2) concerning ADHD patients over 6 years of age and under 18 years of age and controls without mental disorders; (3) at least one of the NLR, MLR, or PLR levels were measured; (4) published in English. The exclusion criteria were as follows: (1) reviews, letters, and conference abstracts; (2) non-human studies; (3) duplicate data; (4) full text was not available; (5) not in English. Two investigators worked independently to complete the preliminary screening through browsing titles and abstracts. The final decisions were made after reviewing the full texts. Disagreements between the researchers were resolved by consultation with the third author.The original data was extracted from the included studies by two of the researchers. The following information was collected: the surname of the first author, publication year, country, matching information for sex and age, diagnostic criteria, sample size, mean age, percentage of men, information about comorbidities, medical treatment and subtypes of ADHD, peripheral blood cell ratios . Any divergences were resolved through discussion between the two investigators and consultation by a third researcher.The quality of the selected studies was independently evaluated by two authors with the Newcastle-Ottawa scale (NOS) . The stu2, I2, and Tau2. Thresholds from Cochrane Collaboration were consistent with interpretation of heterogeneity: 0–40% might be not important; 30–60% may represent moderate heterogeneity; 50–90% may represent substantial heterogeneity, and 75–100% high level of heterogeneity. A fixed-effect model was used to analyze and p < 0.05 was set as a statistical significance. The subgroup analysis with regard to the psychostimulant treatment used was planned.The meta-analysis was conducted using RevMan5  software. Continuous outcomes were pooled as standardized mean difference (SMD). Heterogeneity was evaluated visually on the Forest plot and statistically using the ChiA total of 110 articles were identified through the search strategy. After removing 57 duplicates, 53 remained for titles and abstracts screening. Initially, eleven full-text articles were carefully assessed for eligibility. However, this number was later reduced to eight eligible articles, which were used for data extraction and summarization of the results , 27–30. Among included studies 8, 7, and 6 of them investigated the NLR, PLR, and MLR, respectively. The papers were published between 2018 and 2022. All studies included both male and female subjects. The age of patients ranged from 8.3 ± 1.7 to 10.33 ± 3.15 years old. Seven of these studies were conducted in Turkey, one in Egypt. In all papers ADHD diagnoses were identified based on DSM-V criteria, while in one study additionally with the Schedule for Affective Disorders and Schizophrenia for School-Age Children – Present and Lifetime Version (K-SADS-PL) . PatientNLR in ADHD patients was evaluated in eight studies. The mean NLR were significantly higher in ADHD patients group than in healthy controls in six of them . the difference between groups was not significant in one of the studies , in anot2 = 86%, Chi2 = 28.75, df = 4, Tau2 = 0.12, p < 0.00001). The standardized mean difference (SMD) was 0.49 . Test for overall effect: Z = 2.87 (p = 0.004). The analysis found discrepancies reflected in the considerable heterogeneity of analyzed studies. Specifically, we identified one significant outlier . The result of meta-analysis did not change substantially. SMD was 0.37 , test for overall effect: Z = 2.43, p = 0.02 . The difference between groups was not significant in two of the studies , 24, in 2 = 81%, Chi2 = 21.36, df = 4, Tau2 = 0.08, p = 0.0003). The standardized mean difference (SMD) was 0.31 . Test for overall effect: Z = 2.14 (p = 0.03). The sensitivity analysis was performed and one significant outlier was identified . SMD was 0.17 , test for overall effect: Z = 1.97, p = 0.05  , 28. The2 = 72%, Chi2 = 10.56, df = 3, Tau2 = 0.05, p = 0.01). The standardized mean difference (SMD) was 0.22 . Test for overall effect: Z = 1.63 (p = 0.10)  .Four of the studies evaluated these inflammatory markers in ADHD subtypes , 24, 27.The mean NLR and PLR values with regard to the subtypes of ADHD were assessed in four of the studies. There were no statistically significant differences in these values among the subtypes of ADHD in all of them  , 24, 27.The mean MLR value in context of ADHD subtypes was assessed in three of the studies. There was no statistically significant difference in MLR value among the subtypes of ADHD in three of them  , 24, 27.Only one study assessed patients with ADHD on medical treatment (85% participants) . This stThe correlation between inflammatory markers and scores on clinical scales was assessed in three studies. One of the studies showed no associations between NLR and PLR and T-DSM-IV-S scores  . Anotherp = 0.002). Nevertheless, parent-rated inattention, oppositional and conduct disorder symptoms did not correlate significantly with any of the peripheral inflammatory markers. Teacher-rated hyperactivity/impulsivity, oppositional behaviors and conduct disorder symptoms correlated significantly with PLR  (One study assessed correlation between inflammatory markers and parent/teacher-rated symptoms on T-DSM-IV-S . Parent-ctively) .The present study aimed to systematically review and meta-analyze data on the association between - morphology-derived parameters - NLR, PLR, and MLR values and ADHD. To the best of our knowledge, this is the first systematic review and meta-analysis examining the above-mentioned associations in ADHD.This study demonstrated that NLR and PLR values are higher in ADHD patients as compared to healthy controls. Undoubtedly, prospective clinical studies would be needed to confirm the role of these parameters as markers in ADHD; however, retrospective studies to date indicate the possibility of such potential use. These findings, however, may point to the involvement of inflammation in the pathogenesis of ADHD. NLR is a marker of systemic inflammation that links two different immune pathways. Neutrophils are front-line cells of innate immune defense and engage in a variety of physiological and pathological processes, such as inflammation, autoimmunity, and others . While mOnly one study included patients treated with psychostimulants. No significant difference was determined between patients who received psychopharmacological treatment for ADHD and patients that did not with regard to NLR and PLR. However, this study was an outlier contributing significantly to the heterogeneity in the meta-analysis comparing ADHD patients with healthy controls, suggesting that psychostimulant treatment may affect peripheral inflammatory markers . Some prOur study did not find any significant association between NLR, PLR, and MLR, and specific subtypes of ADHD diagnosis. These result suggest that increased inflammation may be a feature of overall ADHD diagnosis rather than specific subtypes. Our finding are consistent with those of other studies on inflammatory markers in ADHD. No difference in Il-6, TNF-α and morning cortisol measurement was observed between combined and inattentive ADHD subtypes , 41. AddAs regards the relationship between inflammatory markers and ADHD symptoms, this issue remains unclear. In study conducted by Oates et al., elevated levels of IL-13 were associated with inattention, while elevated levels of IL-16 were associated with hyperactivity. Oppositional symptoms were found to be associated with a decrease in IL-2. Furthermore, an increase in IL-16 and a decrease in TNF-α and IL-6 were positively correlated with commissions errors . In our Current treatment of ADHD involves symptom reduction and is purely symptomatic. Investigating the role of inflammation in the pathogenesis of ADHD may contribute to the development of new therapies. To date, no study has been conducted to assess the efficacy of anti-inflammatory treatment in ADHD, with used e.g., non-steroidal anti-inflammatory drugs (NSAIDs). Clinical trials have confirmed the efficacy and safety of NSAIDs in other mental disorders in which inflammation plays a role in the pathogenesis, such as mood disorders , 43. HowIn recent years, the number of adults diagnosed with ADHD has been increasing . To dateOur study has certain limitations, that should be acknowledged. Firstly, the correlations presented may not demonstrate a causal relationship. Elevations in inflammatory markers may indicate the role of inflammation in the pathogenesis of ADHD; however, it is also possible that ADHD develops independently and that its particular features, such as hyperactivity, lower social functioning status, or hygiene, contribute to the increase of these markers. Therefore, careful interpretation of the results is required to understand the complex association between ADHD and inflammatory markers. Secondly, with the exception of one study, all the included studies were conducted within the same country. A recent meta-analysis demonstrated that individuals with depression in Turkey and China displayed significantly higher NLR values compared to other countries. Conversely, PLR was higher among individuals from China rather than Turkey . This inThe original contributions presented in this study are included in this article/supplementary material, further inquiries can be directed to the corresponding author.AG: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Writing – original draft, Writing – review and editing. SM: Data curation, Investigation, Writing – original draft. MG: Data curation, Investigation, Writing – original draft. AA: Funding acquisition, Supervision, Writing – review and editing. PM: Project administration, Supervision, Writing – review and editing. MD: Funding acquisition, Project administration, Supervision, Writing – review and editing.


Attention-deficit/hyperactivity disorder (ADHD) and related impairments persist into adulthood for approximately two-thirds of people diagnosed in childhood . ADHD meUntil recently, Australian adults with ADHD diagnosed after the age of 18 years were only eligible for subsidised access to immediate-release forms of dexamfetamine and methylphenidate. On the contrary, adults who were diagnosed in childhood could access all publicly subsidised ADHD medicines, including atomoxetine, guanfacine, lisdexamfetamine and long-acting methylphenidate. On 1 February 2021, Australia’s Pharmaceutical Benefits Scheme (PBS) listing for lisdexamfetamine was expanded to allow use in adults with ADHD persisting from childhood, even when diagnosed after 18 years of age. Lisdexamfetamine, a pro-drug of dexamfetamine, with a 12–13 hour duration of action is taken once daily, compared with immediate-release stimulants that require dosing two to three times per day.Prior to these subsidy changes, an estimated 20,000 Australian adults were paying more than $1200 (AUD) per person each year for privately funded lisdexamfetamine treatment . ExpansiHere, we provide contemporary prevalence and incidence estimates for ADHD medicine use among adults in Australia for 2021. We describe the changes in dispensing of subsidised lisdexamfetamine and other subsidised ADHD medicines for adults following the expanded PBS-listing of lisdexamfetamine.Services Australia maintains a dataset that includes all PBS dispensing claims for a randomly selected 10% sample of PBS-eligible Australians. We used the PBS 10% sample dataset to examine monthly dispensing rates of subsidised ADHD medicines between 1 February 2016 and 31 January 2022, among adults aged 18 and over. For the year 2021, we estimated the annual prevalence and incidence as described in our previous study .We used an interrupted time-series analysis to quantify changes in monthly dispensing following the lisdexamfetamine listing change on 1 February 2021. We calculated monthly dispensing rates by first multiplying the number of dispensings in each month by 10 before dividing by the estimated population of adults, interpolated from the Australian Bureau of Statistics quarterly population estimates . We modehttps://github.com/ClaudiaBruno/Lis_res_letter.We stratified analyses by ADHD medicine, age group and patient sex. We present all estimates per 1000 population and conducted our analyses using R version 4.2.1 . The code used in the analysis can be found at The New South Wales (NSW) Population and Health Services Research Ethics Committee approved this study  and the Australian Government Services Australia External Request Evaluation Committee granted data access .From 1 February 2016 to 31 January 2022, there were approximately 3,486,870 ADHD medicine dispensings to 199,280 adults . In 2021, the annual prevalence of ADHD medicine use was 6.8 per 1000 adults; it was higher among people aged 18–24 years (19.0 per 1000) than those ⩾ 25 years (5.5 per 1000). New use (incidence) was greater among females than males across both age groups, and lisdexamfetamine was the most initiated ADHD medicine followed by dexamfetamine .We found the public subsidy change was associated with an immediate and sustained increase in monthly lisdexamfetamine dispensings of 37% , with an increase in trend through to the end of the study period of an additional 5% per month  on top of pre-existing monthly increases of 3.14% (95% CI: [3.04%– 3.23%]). Specifically, the mean monthly dispensing rate for lisdexamfetamine increased to 1.2 per 1000 adults in the 12 months following the intervention compared to 0.4 per 1000 in the 12 months prior. We did not observe either step or trend changes in other stimulant (dexamfetamine and methylphenidate) or non-stimulant medicine dispensing. While immediate and sustained increases in lisdexamfetamine dispensing were similar for females and males , females had higher trend increases through to the end of the study period of 7% per month  compared to males 4%  .It is clear from our analysis that expanding subsidy listing of lisdexamfetamine resulted in increased dispensing of subsidised lisdexamfetamine among adults with ADHD. Furthermore, lisdexamfetamine dispensing continued to rise each month throughout the following year at an increased rate. Less clear are the underlying prescribing phenomena driving these changes. The immediate and sustained increase in dispensing is unlikely to be related to an immediate increase in new people treated. More likely, this is due to people switching from unrecorded privately prescribed lisdexamfetamine to the public market. This could be confirmed using medicines sales data or State and Territory stimulant prescription monitoring data.Continued monthly increases in lisdexamfetamine following this initial jump in dispensings may represent increasing awareness of ADHD persisting into adulthood among psychiatrists, general practitioners, and the public leading to improved recognition and diagnosis. The use of lisdexamfetamine for all ages was already increasing before the subsidy listing was expanded , and thiNotwithstanding increases in lisdexamfetamine, the rates of ADHD medicine use in adults in 2021 remain below the estimated prevalence of ADHD . Followi


Autistic traits (ATs) are frequently reported in children with Attention-Deficit/Hyperactivity Disorder (ADHD). This study aimed to examine ATs in children with ADHD from both behavioral and neuroimaging perspectives.We used the Autism Spectrum Screening Questionnaire (ASSQ) to assess and define subjects with and without ATs. For behavioral analyses, 67 children with ADHD and ATs (ADHD + ATs), 105 children with ADHD but without ATs (ADHD − ATs), and 44 typically developing healthy controls without ATs (HC − ATs) were recruited. We collected resting-state functional magnetic resonance imaging (rs-fMRI) data and analyzed the mean amplitude of low-frequency fluctuation (mALFF) values (an approach used to depict different spontaneous brain activities) in a sub-sample. The imaging features that were shared between ATs and ADHD symptoms or that were unique to one or the other set of symptoms were illustrated as a way to explore the “brain–behavior” relationship.Compared to ADHD-ATs, the ADHD + ATs group showed more global impairment in all aspects of autistic symptoms and higher hyperactivity/impulsivity (HI). Partial-correlation analysis indicated that HI was significantly positively correlated with all aspects of ATs in ADHD. Imaging analyses indicated that mALFF values in the left middle occipital gyrus (MOG), left parietal lobe (PL)/precuneus, and left middle temporal gyrus (MTG) might be specifically related to ADHD, while those in the right MTG might be more closely associated with ATs. Furthermore, altered mALFF in the right PL/precuneus correlated with both ADHD and ATs, albeit in diverse directions.The co-occurrence of ATs in children with ADHD manifested as different behavioral characteristics and specific brain functional alterations. Assessing ATs in children with ADHD could help us understand the heterogeneity of ADHD, further explore its pathogenesis, and promote clinical interventions.The online version contains supplementary material available at 10.1186/s12993-023-00222-x. Diagnostic and Statistical Manual of Mental Disorders (DSM-5) [Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neurodevelopmental disorder that is characterized by inattention, hyperactivity, and impulsivity. The fifth edition of the  (DSM-5)  no longe (DSM-5) . Even wh (DSM-5) .ATs represent stereotypy and deficits in social interactions, usually defined by positive results on ASD scales. Nevertheless, ATs per se do not meet the clinical threshold for ASD diagnosis , 5. In yIn addition to the above-mentioned behavioral and cognitive evidence, some studies have tried to investigate ATs in children with ADHD based on brain imaging data to explore the potential underlying neurobiological mechanisms. Most evidence has come from studies comparing ADHD and ASD probands to explore potential overlapping and distinctive brain structural and/or functional alterations. Subcortical-volume changes might be the same between ADHD and ASD, while cortical thickness changes might or might not be the same between the two conditions . Fractio. explored white-matter (WM) microstructural characteristics of ATs in patients with ADHD. They found that AT-related changes to WM were mainly located in the right posterior limb of the internal capsule/corticospinal tract, right cerebellar peduncle, and midbrain [. found that cerebral blood flow in the left middle frontal gyrus was correlated with both ASD and ADHD scores, while that in the left temporal pole was negatively correlated with ASD score, in children and adolescents with comorbid ADHD and ATs. However, their post hoc analysis revealed nonsignificant differences in these clusters between the ADHD groups with and without ATs [Few studies thus far have directly investigated AT-related changes in brain imaging. A study of structural brain images showed a positive relationship between ASD score and gray-matter volume in adults with ADHD . Althougmidbrain , while Amidbrain . Zhang ehout ATs . One stuhout ATs . The aboResting-state functional magnetic resonance imaging (rs-fMRI) is a non-invasive tool used to probe the spontaneous neural activity of intrinsic human-brain functional organizations, which likely reflects disorder etiology . AmplituIn summary, ATs are common in ADHD and can affect the behavioral, cognitive, and brain features of the disorder. To our knowledge, the neuroimaging mechanism of ATs has not been well illustrated. Therefore, in the present study we aimed to investigate ATs in children with ADHD in terms of both behavioral expression and brain functional alterations to explore the “brain–behavior” relationship, which could promote better understanding of AT-related heterogeneity in children with ADHD. To analyze brain functional alterations, the ALFF in rs-fMRI was used. We hypothesized that ATs in children with ADHD would be associated with more ADHD symptoms and with specific brain imaging changes.vs. 8.84 ± 1.71; P = 0.0027) and ADHD − ATs , ADHD + ATs  subgroups. Full-Scale Intelligence Quotient (FSIQ) scores were higher in HC − ATs than ADHD overall group  and in ADHD − ATs , ADHD + ATs  subgroups. No difference was found between ADHD + ATs and ADHD − ATs in distributions of age, FSIQ, or ADHD subtypes.Demographic and clinical characteristics of the two groups  or three groups  are listed in Table For AT symptoms, totals and sub-scores of the Autism Spectrum Screening Questionnaire (ASSQ), were significantly higher in children with ADHD than in HC − ATs, except for the communication problems Table . InteresFor ADHD core symptoms, totals and sub-scores of the Swanson, Nolan, and Pelham rating scale, version IV (SNAP-IV) were significantly higher in children with ADHD than in HC − ATs. Post hoc analyses among the three groups showed that SNAP-IV totals and sub-scores were higher in the two ADHD groups than in HC − ATs. In our comparison between subjects with ADHD, ADHD + ATs had more HI symptoms than ADHD − ATs Table , whereasr = 0.299, P = 7.7E−05), communication problems , and RRBs . However, the above relationship was not seen in HC − ATs .Based on the above findings, we further explored the relationship between HI symptoms and ATs in children with ADHD using partial-correlation analysis after controlling for age, sex, and FSIQ. HI symptoms showed significant positive correlation with social-interaction score  and females (n = 26) in AT symptoms, including the ASSQ totals  and all the three subscales: social interaction , communication problem , RRBs . In addition, no sex difference was found for ADHD core symptoms, including the SNAP-IV totals  and the two subscales: inattention , HI . Further, we also found no differences in totals and all sub-scores of ASSQ and SNAP-IV scales between males and females in both ADHD − ATs and ADHD + ATs subgroups .To address the potential influence of sex on our present findings, we used two sample Demographic and clinical characteristics of subjects included in the imaging analyses are shown in Additional file F = 10.259, P = 9.200E−5), right MTG , left middle occipital gyrus , right parietal lobe (PL)/precuneus , and left PL/precuneus  values: in the left middle temporal gyrus , left MOG (Cluster 3), and left PL/precuneus (Cluster 5) might be specifically associated with ADHD  might be unique to ATs. These were the only differences we found between ADHD + ATs and the other two groups, but a nonsignificant difference was found between ADHD − ATs and HC − ATs  might be common to both ADHD and ATs, albeit in diverse associated directions  analysis of the ADHD groups. SNAP-IV and ASSQ total scores were set as covariates when analyzing the association of ATs and ADHD core symptoms with brain functional alterations, respectively.P = 0.0006, 0.0073, and 0.0004 for social interaction, communication problems, and RRBs, respectively). In contrast, mALFF values in the right MTG (Cluster 2) were found to correlate positively with RRBs (P = 0.0035) and communication problems  on all three subscale scores . For HCs, they were recruited from different local elementary schools in Shenzhen by advertisements. A total of 172 medication-naïve patients with clinically diagnosed ADHD based on the DSM-IV from the outpatient department of SCH from June 2017 to December 2020, and 45 HCs were recruited. This cross-sectional study was approved by the Medical Ethics Committee of SCH, and informed consent was obtained from all participants and their parents.Patients came to the clinic on their first visit. They underwent a semi-structured clinical interview that used the Kiddie Schedule for Affective Disorders and Schizophrenia Present and Lifetime Version (K-SADS-PL) to confirm the diagnosis of ADHD and exclude other psychiatric disorders . InclusiAll participants’ parents were asked to complete the SNAP-IV and ASSQ scales for ADHD and ASD symptom evaluation. Subjects with a total score of ASSQ ≥ 12 were defined as having ATs . The ADHe.g., cysts) during MRI scans, or excessive head motion with > 3 mm of translation or > 3° of rotation in any direction, led to exclusion for brain analysis. Five children with ADHD were excluded for further imaging analyses due to their excessive head motion.For the imaging analyses, only subjects who agree to participate and met the following criteria were included for data acquisition: (1) right-handed; (2) do not have metal implants (including non-removable dentures); (3) not suffering from claustrophobia. Any visible abnormalities on MRI images as examined by an experienced radiologist  and sufficient sensitivity (0.87) and specificity (0.79) [We used the SNAP-IV parent form to evaluate ADHD symptoms. The form includes 18 items on a three-point rating scale . The Chinese version of SNAP-IV has been demonstrated to be a reliable and valid instrument, with satisfactory reliability  .α = 0.86) [The ASSQ consists of 27 items on a three-point rating scale . Nine items were designed for social interaction, 7 for communication problems, and 11 for RRBs . The ASS = 0.86) . To defi = 0.86) .We acquired rs-fMRI data of children at SCH using a Siemens Skyra scanner  with a standard 12-channel head coil. Functional images were acquired using an echo-planar imaging sequence with the following parameters: repetition time = 2000 ms, echo time = 30 ms, flip angle = 90°, thickness/skip = 3.5/0.7 mm, matrix = 64 × 64, field of view = 200 × 200 mm, 33 axial slices, 240 volumes, and 3 × 3 mm in-plane resolution. All participants were asked to close their eyes without falling asleep during the 8 min of fMRI scanning.3), spatial smoothing with a 6-mm full-width-at-half-maximum Gaussian filter, linear detrending, and nuisance covariate regression  [We acquired resting-state functional images using RESTplus  on the M signal) .For higher test–retest reliability in gray matter regions and more sensitive for discerning differences between individuals and groups , ALFF, rt-test, or variance (ANOVA) and post hoc analysis with the least-significant-difference (LSD) t-test, χ2 test, or Fisher’s exact test were used to compare the demographic and clinical characteristics of the HC − ATs and ADHD two groups or HC − ATs, ADHD − ATs and ADHD + ATs three groups. We used general linear-model analysis with sex, age, and FSIQ as covariates, or analysis of covariance (ANCOVA) and post hoc analysis with the LSD t-test, to compare AT symptoms and ADHD symptoms between subjects with ADHD and HC − ATs or among the three groups. Partial-correlation analysis with sex, age, and FSIQ as covariates was used to separately explore the relationships between AT symptoms and ADHD symptoms in the ADHD and HC − ATs groups.For behavioral data, analysis of two sample  P < 0.01 and cluster size ≥ 42 [t-test: relationships between mALFF values of different brain regions and symptoms as assessed by ASSQ and SNAP-IV were investigated using stepwise multiple linear-regression analyses, after elimination of factors whose variance inflation factor values were > 10.For neuroimaging data, we used ANCOVA and RESTplus to compare the mALFFs of children in the ADHD + AT, ADHD − AT, and HC − AT groups, with sex, age, and FSIQ as covariates. The multiple-comparison correction was based on Analysis of Functional NeuroImages’s AlphaSim, with a threshold ofize ≥ 42 . We thenP < 0.05 was considered significant.We performed all behavior and mALFF value statistical analyses using SAS version 9.1  and SPSS version 23 . Additional file 1:Table S1. Demographic characteristics of groups for neuroimaging analysis. Figure S1. Differences in mALFF values among the three groups .


To determine whether more patients presented with Attention-deficit/hyperactivity disorder (ADHD)-related visits and/or sought care from family physicians more frequently during the COVID-19 pandemic.Electronic medical records from the University of Toronto Practice-Based Research Network were used to characterize changes in family physician visits and prescriptions for ADHD medications. Annual patient prevalence and visit rates pre-pandemic (2017–2019) were used to calculate the expected rates in 2020 and 2021. The expected and observed rates were compared to identify any pandemic-related changes.The number of patients presenting for ADHD-related visits during the pandemic was consistent with pre-pandemic trends. However, observed ADHD-related visits in 2021 were 1.32 times higher than expected (95% CI: 1.05–1.75), suggesting that patients visited family physicians more frequently than before the pandemic.Demand for primary care services related to ADHD has continued to increase during the pandemic, with increased health service use among those accessing care. The COVID-19 pandemic has disrupted the daily lives of people living in Ontario, Canada and worldwide. On March 17, 2020, Ontario declared a state of emergency due to COVID-19. From March 14, 2020 to May 15, 2021, Ontario schools were closed for 20 weeks in total, much longer than any other Canadian province or territory .Evidence from international systematic reviews and/or meta-analyses in the general population during the COVID-19 pandemic has consistently demonstrated that the general population experienced mental health symptoms –9. A sysADHD is a childhood-onset neurodevelopmental disorder and one of the most common childhood psychiatric conditions in Canada , 16. ADHSeveral studies have reported on the worsening of ADHD symptoms during the COVID-19 pandemic. A Canadian online survey to caregivers of children with ADHD aged 5–18 years (n = 587 surveys) revealed that during the COVID pandemic, parents reported that their children with ADHD experienced greater ADHD symptoms, depression and anxiety . This fiFor most Canadians seeking healthcare for mental health conditions, including ADHD, their family physician is the first point of contact. The Canadian Paediatric Society (CPS), American Academy of Pediatrics (AAP) and Canadian ADHD Resource Alliance (CADDRA) have all stated that ADHD care including diagnosis and management is within the practice of family physicians –27. A crWe observed an increase in patient inquires into ADHD across the lifespan in family medicine practices in Ontario, Canada during the COVID-19 pandemic, so we set out to examine the trend of patient visits and prescriptions for ADHD prior to (2017–2019) and during the pandemic (2020–2021). We aimed to determine the extent to which this increase was the result of a greater number of visits per patient presenting with ADHD as the most responsible reason for the visit to the primary care physician and/or an increase in the number of patients presenting for ADHD-related visits. Our research questions are: 1) did health service use for ADHD increase in the primary care setting during the COVID-19 pandemic, and/or 2) did the prevalence of ADHD-related visits increase during the COVID-19 pandemic?We conducted a retrospective study of family medicine patients in the University of Toronto Practice-Based Research Network (UTOPIAN) from January 1, 2017-December 31, 2021. We used data from the UTOPIAN Data Safe Haven (dfcm.utoronto.ca/utopian-data-safe-haven), a primary care EMR database with records collected from family physician practices in the Greater Toronto Area and beyond in Ontario, Canada. Records that meet minimum data quality criteria , 33. PriEligibility was assessed at the end of each calendar year, recognizing that some patients will join and leave a family medicine practice over time. Patients were enrolled in the cohort based on the following criteria: 1) they were registered to a physician for whom the data extracted met minimum quality criteria, 2) they had age and sex recorded in the EMR, 3) they had at least one billing code for an office or virtual visit with a family physician , 35, 36 We assessed primary care health utilizations for ADHD using three outcome measures: 1) total number of ADHD visits with Ontario Health Insurance Program (OHIP) billing code 314 for ADHD and the International Classification of Diseases Ninth revision (ICD-9) code also uses 314 for ADHD, per 1000 patients as a measure of service demand on the health care system; 2) total number of patients with at least one billing for a visit  with a dThe UTOPIAN database includes measures of demographic characteristics . Neighborhood-level income quintiles and rurality were derived based on the patient’s residential postal codes using Statistics Canada’s Postal Code Conversion Files .We employed a repeated cross-sectional design to describe the annual visit and patient prevalence rates from January 1, 2017- December 31, 2021. To evaluate whether the COVID-19 pandemic had a significant impact on primary care services for ADHD, we used data from the years before the pandemic (2017–2019) to predict the expected rates in 2020 and 2021 during the pandemic. We used Poisson regression with exchangeable correlation structure to account for the clustering of count data. In particular, the Poisson regression was used to estimate the expected count for i) total number of visits for ADHD, ii) total number of patients with at least one ADHD-related visit, and iii) the total number of patients with at least one ADHD-specific medication prescribed each year. The log of total number of patients enrolled in the cohort each year was used as an offset term. We hypothesized that the prevalence of ADHD differs by age and sex, and we performed subgroup analyses using Poisson regression by stratifying for age group and sex, while adjusting for income quintiles and rurality. The expected counts in 2020 and 2021 were reported using the sub-group analysis (i.e. stratified Poisson regression). We compared the expected and observed counts in 2020 and 2021 using two-sided z-test with statistical significance evaluated at 5% alpha-level and reported 95% confidence intervals (CI). Statistical analyses were performed using SAS software version 9.4.This study was approved by the Research Ethics Boards of the University of Toronto (#40129) and North York General Hospital (#20–0044). Physicians in this study provided written informed consent to have their EMR data extracted, de-identified, and used for research purposes; patients can opt out of uses for research.A total of 266,208 patients met criteria for inclusion  in 2017 to 5.4  in 2019 . Based oAlthough the observed rate of 7.6  in 2020 was within the expected range, the observed rate of 10.5  in 2021 was 1.32; 95% CI: 1.05–1.75, times higher than expected . FurtherDespite the higher number of ADHD visits during the pandemic, the number of unique patients with at least one visit for ADHD per year remained consistent with pre-pandemic trends. The annual prevalence of patients visiting for ADHD increased steadily from 2.4 per 1000 patients in 2017 to 5.5 per 1000 patients in 2021 .The observed rates in 2020 and 2021 were within the expected range based on pre-pandemic trends , with siIn the longitudinal cohort (from 2017 to 2021), we found 56,224 unique prescriptions for ADHD medications. Of these, 19,206 (34.1%) occurred on the same date as a billing with a diagnostic code for ADHD; less specific diagnostic codes for behavior disorders of childhood and adolescence were also frequently used when prescribing these medications. We observed that the prescribing of ADHD medications on the same day as a patient visit for those aged 5–55 years of age was most associated with the OHIP billing code, 313 representing behavioural disorders of childhood and adolescence (21–24%) during the pre-pandemic period from 2017–2019 followed by the OHIP billing code 300 representing anxiety (19–20%) then 314 for ADHD (18–20%). During the pandemic period from 2020–2021, the most frequent OHIP billing code was 314 for ADHD (25%) followed by 313 for behavioural disorders of childhood and adolescence (22–24%) then 300 for anxiety (22–23%). We found a somewhat similar pattern of OHIP billing codes in the pre-pandemic period for children/adolescents. The most frequent OHIP billing code was 313 for behavioural disorders followed by 314 for ADHD and then 300 for anxiety, and this pattern was consistent during the pandemic period. For adults during the pre-pandemic period, the most frequent OHIP billing code was 300 for anxiety, followed by 313 for behavioural disorders then 314 for ADHD. During the pandemic period, the most frequently billed code for adults remained as 300 for anxiety followed by 314 for ADHD and then 313 for behavioural disorders. The annual prevalence of patients being prescribed medication for ADHD increased from 12.9 per 1000 patients in 2017 to 21.9 per 1000 patients in 2021 .The prescription rates observed during the COVID-19 pandemic were within the expected range 2020 and 2021 based on pre-pandemic trends .In general, male patients had a higher annual rate of ADHD-related visits , ADHD-reDuring the COVID-19 pandemic in 2021, we observed a 32% overall relative increase in the total number of visits to family physicians for ADHD for ages 5–55 years in Ontario, Canada compared to the expected number of visits. This was in addition to the growing demand for ADHD-related services that existed even before the pandemic. This reflects an increase in the intensity of health service utilization in the primary care setting for those seeking care related to ADHD. Similar findings have been observed for other mental health services related to anxiety and depression . There wWe found that females in the age groups 5–9 years and those between 20–55 years visited their family physicians more frequently during the pandemic period in 2021 compared to the pre-pandemic period. In the younger age group, parents likely sought greater support from their family physicians for their female children related to ADHD and this could have stemmed from school closures, remote learning, and social isolation. Older females may have had greater responsibilities to cope with not only related to changes in education and learning during the pandemic but also with employment and parenting/family obligations which may have led to seeking more health care related to ADHD . It may The number of people diagnosed with ADHD and prescribed medication to treat ADHD has increased in recent years. A retrospective cohort study involving the population of Quebec from 2000–2018 demonstrated a steady increase in prevalence of ADHD among children and young adults . In addiThe early stages of the pandemic in 2020 did not necessarily coincide with an increase in mental health presentations to family physicians but the adaptation to the new conditions imposed by the COVID-19 pandemic increased workloads on the frontline of mental health services offered in the Canadian primary care setting . Our stuWhile family physicians are the gatekeepers of health care in Ontario, Canada for patients seeking ADHD services, family physicians are facing challenges in accurately identifying, diagnosing, and managing ADHD in the primary care setting. Individuals with ADHD require more specialized care pathways beyond what is typically available in a family physician’s practice. This means that greater support and resources may be needed in primary care to support all family physicians in providing the comprehensive care that is needed to individuals with ADHD across all ages. Such care should be readily accessible, timely and integrated with other health care professionals such as psychiatrists, psychologists, behaviour health specialists, nurses and even schools. More focus on integrated care models in primary care may be needed so that family physicians can become better equipped to handle the demands of increased health care services for ADHD. Future research on the delivery of integrated health care services in primary care to meet the demands of individuals with ADHD should be explored.This study has certain strengths. It used EMR data from a large primary care database in Ontario to examine ADHD medication trends in ages 5–55 years prior to and during the pandemic, a feature that is unique to the UTOPIAN Data Safe Haven database. Other provincial health administrative databases for medications in Canada may not have information about prescriptions for all age groups. This study also provided data on the pandemic period which spanned from March 2020 to December 2021, capturing a total period of 22 months where other published studies have reported on the immediate impact of the pandemic over a much shorter time , 42, 49.We saw an increased demand on family physicians to provide mental health services for those presenting with ADHD-related visits during the second year of the COVID-19 pandemic. While primary care is the first point of access for most patients seeking ADHD care in Ontario, Canada, family physicians were assessing patients for ADHD-related visits more frequently than before the COVID pandemic. Given the significant degree of impairment on academic, social, and/or occupational functions that patients presenting with ADHD face across the ages coupled with the trends that we observed for increased visits to primary care physicians as we continue living with the pandemic suggest that resources to support family physicians may be needed.S1 Appendix(RTF)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


Bartonella spp. and Anaplasma spp. are related to this zoonotic dynamic.Evidence suggest that wildlife Infectious diseases related to wildlife are of most importance because of the agents’ capacity to spill over into humans from the wild reservoir. Among them, the bacteria Didelphis marsupialis; spleen, liver, and skin of Pecari tajacu; spleen, liver, and skin of Chelonoidis denticulata.The primary goal of the present study was to determine the presence of pathogenic bacteria in kidney and liver tissues of Bartonella spp. with subsequent genetic sequencing were used.A PCR using universal and specific primers for 16 S rRNA, of Bartonella vinsonni was detected in the liver tissue of Didelphis marsupialis using both universal primers and those specific for Bartonella sp. Anaplasma platys was detected at the liver and spleen level using universal primers. Additionally, Bartonella spp. was found at the liver, spleen, and skin level in Pecari tajacu using the specific primers. Finally, using the universal and specific primers at the skin level, Bartonella spp. was evident in Chelonoidis denticulata.The results in this study indicate that Bartonella vinsonii was detected at the liver tissue in Didelphis marsupialis. DNA of the Anaplasma platys and Bartonella spp. were identified at the spleen and liver level. This study also identified that DNA Bartonella spp. was detected in Pecari tajacu skin. Finally DNA of Bartonella spp. was evident in Chelonoidis denticulate skin. The findings of this study suggest that these bacteria are present in these animals and may be responsible for outbreaks.The presence of the DNA of the  Bartonella sp. and Anaplasma sp. Moreover, there is evidence that these bacteria can be transmitted from different animals to humans [Human activities play critical role in the infectious diseases originating in wildlife. Previous studies have found that human and domestic animal intrusion impact in wildlife ecology , 2. The o humans .Bartonella is a bacterial genus that involves some species that are pathogenic for humans, such as Bartonella bacilliformis, Bartonella henselae, and Bartonella quintana, as well as others that are potentially pathogenic, including Bartonella elizabethae, Bartonella tamiae, and Bartonella vinsonii, subspecies aurapensis [B. vinsonii subsp. arupensis was first isolated in a case of bacteremia in a rancher, in Wyoming-USA [Peromyscus maniculatus. This bacterium is an important component for public health because it carries hantavirus which can be transmitted to humans [B. vinsonii subsp. Arupensis is a causative agent of endocarditis and febrile processes in humans and dogs [rapensis , 5. It hming-USA , and haso humans . Additioand dogs –13.Anaplasma is a proteobacterium that multiplies at the intracellular level is widely distributed in tropical, subtropical and temperate regions. A number of studies have postulated that Anaplasma can cause anaplasmosis in variety of animals including ruminants, rodents, birds, and humans [Anaplasma sp . are zoonotic pathogens and are transmitted by ticks generating a problem for both Veterinary and Public Health [d humans –16. Detad humans . Four spc Health .Pecari tajacu and Chelonoidis denticulata. Three samples of Didelphis marsupialis were collected from Atalaya  . The sample were taken from the liver, spleen, and skin of Previously, 50 ug of tissue was digested using 200 µl of lysis buffer , and was incubated at 52 °C overnight until all tissue fragments were completely dissolved. Further extraction and purification procedures were performed using a commercial extraction kit . The bacterial DNA obtained after extraction was diluted in 100 µL of nuclease-free water and, then, processed or stored at -20 °C until use.Bartonella genus and the other with universal primers. All samples were used with specific primers for Bartonella as universal.Two different PCR approaches for 16 S rRNA were used: one with specific primers for Bartonella genus was amplified in blood samples (P24Emod CCTTCAGTTMGGCTGGATC- 16 S-R GCCYCCTTGCGGTTAGCACA) [A 438-bp fragment of the 16 S rRNA gene specific to the TAGCACA) , 19. TheIn the case of amplifying any bacteria, the molecular diagnosis was confirmed by amplification and sequencing of a 1503-bp region of universal 16 S rRNA gene fragments using universal primers (8 F AGAGTTTGATCCTGGCTCAG- 1510R GGTTACCTTTGTTACGACTT) , 20. AllDNA sequences were analyzed using the BLAST analysis tool and compared with the GenBank database.B. vinsonni in the spleen of D. marsupialis “Opossum” (1 case), Bartonella spp in the skin of C. denticulata “Yellow-footed tortoise” (1 case), and Anaplasma spp in the spleen and liver of P. tajacu (1 case).All samples were analyzed by molecular techniques. Table Bartonella spp., PCR approaches of the 16 S rRNA gene specific to the Bartonella were performed on all samples. Sequence analysis showed the presence Bartonella vinsonni-positive sample in the spleen of D. marsupialis. Further analysis showed that Bartonella spp. was identified in the liver, spleen and skin in P. tajacu. However, Bartonella spp. was only observed in the skin of C. denticulata  microplus [A. platys was identified in R. sanguineus demonstrating the critical role of ticks in transmitting the bacterium Anaplasma sp. to the animals [A. platys and A. capra were observed in R. microplus collected from goats, cattle, and sheep [A. platys were found in dogs and R. sanguineus [A. phagocytophilum in dogs, horses and ticks such as Ixodes ricinus, Hyalomma scupense, and H. marginatum. The same report found Anaplasma spp. and A. ovis in goats and sheep [A. platys was identified in dogs and Anaplasma sp. in sheep [In our study, icroplus . An impl animals , 23. Thend sheep , 24; Thenguineus , 24. Simnd sheep –28. Whilin sheep .Anaplasma spp. in animals of the Xenarthra superorder, specifically in Bradypus tridactylus, B. variegatus, Choloepus didactylus, Tamandua tetradactyla, Myrmecophaga tridactyla, Cabassous unicinctus, Dasypus novemcinctus, and Euphractus sexcinctus. Additionally another study showed the prevalence of Anaplasma spp. in several species of wild carnivorous animals, indicating the potential risk of the bacterium into humans whenever they encounter wild animals for tourism, consumption, tourism or other extractive activities [Anaplasma spp. was identified in the spleen and liver of P. tajacu, therefore this could be considered as reservoir. Further studies are necessary for detecting the bacteria in culture and elucidating the role of ectoparasites such as R. microplus ticks that were detected infesting P. tajacu [In South America, a study in Brazil identified tivities , 30, 31.. tajacu .Bartonella sp. was identified at the liver, spleen, and skin level in P. tajacu. The identification of Bartonella related to this animal is reinforced by the previous study in which B. bacilliformis was detected in the ectoparasites of P. tajacu such as R. microplus [P. tajacu for consumption.In our study, icroplus . It can B. vinsonii was found at the spleen level in Didelphis marsupialis. This animal could be involved in the zoonotic chain of this bacterium. For example B. vinsonii has been reported in animals such as Canis latrans “coyote” as a reservoir where this bacterium could generate endocarditis in humans [B. vinsonii in carnivores such as Canis latrans “coyote”, Vulpes vulpes “Red Fox”, and Procyon lotor “Raccoon” [B. v. berkhoffii and B. rochalimae were found in asymptomatic domestic dogs, so they could be reservoirs of risk for human infection [In the current study, n humans , 13. AnoRaccoon” . In Perunfection .Bartonella sp. was also identified in the skin of Chelonoidis denticulata, which presumes that the bacterium can be transmitted to other animals through vectors such as ticks although the species was not determined to identify any potential risk of causing any disease in humans. However, it is known that the Bartonella genus can spill over into different animals, especially from rodents to humans and from rodents to domestic animals [ animals . An implB. vinsonni in spleen from D. marsupialis and A. platys in liver and kidney from P. tajacu. These results are significant due to the risk of infection by these bacteria to people who hunt these wild animals for their meat. As well as the transmission of the infection to domestic animals in areas where the presence of wild animals studied generated bacterial zoonoses.In conclusion, for the first time, we have been able to detect A limitation of this study is that, we can not assure the viavility of these bacteria. A further study should contemplate cultivating these bacteria of tissues such as skin to determine the role of these animals as reservoirs. Also the animals and samples in the present study were a reduced number.


Preterm birth is associated with an increased risk of neurodevelopmental and neurobehavioral impairments including attention-deficit/hyperactivity disorder (ADHD), the most common neurobehavioral disorder of childhood. In this narrative review, we examine the known associations between prematurity and ADHD and highlight the impact of both prematurity and ADHD on multiple domains across the pediatric life-course. We develop a framework for understanding the health services journey of individuals with ADHD to access appropriate services and treatments for ADHD, the “ADHD Care Cascade”. We then discuss the many racial and ethnic inequities that affect the risk of preterm birth as well as the steps along the “ADHD Care Cascade”. By using a life-course approach, we highlight the ways in which inequities are layered over time to magnify the neurodevelopmental impact of preterm birth on the most vulnerable children across the life-course. In the United States, approximately 10.5% of babies are born premature (birth prior to 37 weeks), equating to roughly 385,000 preterm infants born each year ,3,4. WhiIn this narrative review, we explore the impact of prematurity on neurodevelopmental and neurobehavioral outcomes across the life-course, specifically through the lens of attention-deficit/hyperactivity disorder (ADHD), the most prevalent neurobehavioral diagnosis in childhood and adolescence . FurtherAttention-deficit/hyperactivity disorder is a neurobehavioral condition that typically presents in early childhood with symptoms that include hyperactivity, impulsivity, and/or inattention . ADHD isThe prevalence of ADHD diagnosis and treatment in the U.S. has notably increased over the past two decades ,9,10. ThADHD is also the most expensive chronic health condition for children and adolescents. In a large study of 2.9 billion patient records from 183 sources of data, Bui et al. found that ADHD results in USD 20.6 billion in healthcare spending in the United States each year . AdditioThe management of ADHD begins with symptom recognition, either by family members, teachers, primary healthcare providers, or the youth themselves. After symptom recognition, children often present to a healthcare provider for evaluation and potential diagnosis. Following diagnosis, individuals and families ideally partner with their healthcare team to determine treatment plans which can include medication—most commonly, stimulants, selective norepinephrine-reuptake inhibitors, and alpha-2-adrenergic agonists—behavioral therapy, or observation ,13,14. FADHD is a clinical diagnosis; there are no specific cognitive, metabolic, or neurologic markers or tests for ADHD. This presents a potential barrier to uniform detection of symptoms across varying contexts. In fact, some have suggested that ADHD is a cultural construct, defined by cultural, educational, social, and family norms around appropriate childhood behavior . This maThe epidemiologic association between preterm birth and ADHD has been documented across multiple studies and populations. A large birth cohort study of over 110,000 children found that preterm infants had a higher risk of ADHD symptoms compared to their term peers . An analConflicting evidence exists regarding the risk of ADHD among late preterm  infants. Some studies have found no association, while others continue to report a higher risk of ADHD among children born late preterm, albeit a lower risk than very or extremely preterm-born children ,20,22.In addition to the elevated risk of ADHD among preterm-born children compared to term-born children, there are also several risk factors specific to preterm-born children that further increase the risk of ADHD. For example, while small-for-gestational-age  children have a higher risk for ADHD compared to appropriate-for-gestational-age-weight infants, researchers have found that the association between SGA and a diagnosis of ADHD is stronger among preterm-born children . CochranAdditionally, other pregnancy risk factors associated with ADHD in term-born children, such as hypertensive disorders of pregnancy and maternal smoking, were not consistently associated with the development of ADHD in preterm-born children . Social There are also unique characteristics of ADHD among preterm-born children, suggesting a unique subtype and pathophysiology in this population. ADHD is divided into three subtypes: hyperactive or impulsive, inattentive, or combined hyperactive and inattentive. While the combined phenotype is most common in the general population, among preterm-born children, the most common ADHD phenotype is the inattentive subtype ,20. ThisSome have suggested that the increased risk of ADHD among preterm infants may be due to a systematic bias as a result of increased medical monitoring, testing, and screening that children born preterm receive, such as through Early Intervention and high-risk infant follow-up programs that may systematically screen for ADHD symptoms ,26,27. HADHD has a significant and lasting impact across the life-course for children, adolescents, and adults. Most prominently, ADHD has a significant impact on education, schooling, and educational attainment. Children with ADHD are more likely to have a reading, math, or spelling disability. They are also more likely to need to repeat a grade, be expelled, or drop out from school . One stuBeyond schooling, ADHD can affect multiple domains of health-related quality of life for children and adolescents . KlassenFinally, ADHD is also costly for families. One study found that the total financial burden over the course of the development of a child who has ADHD was more than five times greater than children without ADHD ,36. CostThe 2014 National Survey of the Diagnosis and Treatment of ADHD and Tourette Syndrome found that among children 8–17 years of age, 44.3% of families reported one or more negative financial impacts as a result of a child’s ADHD diagnosis. These included reducing work hours and avoiding job changes to ensure adequate health insurance coverage. Over 14% of families reported that a member of the family stopped working due to the needs of the child with ADHD. More severe and earlier diagnosis was associated with a greater financial impact . NotablyADHD can also have financial implications on individuals with ADHD in adulthood. Adults with ADHD are more likely to work entry-level jobs or be unemployed ,32. TheyIt has been noted that the prevalence of ADHD diagnosis decreases with increasing age, though these patterns may not persist for preterm-born children and adults ,37,38. WNotably, the impact of ADHD on psychosocial health, educational attainment, and financial well-being has not been specifically studied among the preterm-born population. For example, while prematurity is associated with costs for families and societal costs, it is not known what proportion of the costs associated with prematurity may be due to ADHD . Due to When considering the life-course impacts of prematurity, it is important to recognize that there are significant racial and ethnic inequities in preterm birth in the United States. Race is a social construct and health differences across racial and ethnic populations are not reflective of biology, genetics, or individual behavior. Rather, these differences represent the effects of structural, institutional, interpersonal, and internalized racism ,42,43,44Following discharge from the Neonatal Intensive Care Unit (NICU), Black and Hispanic/Latinx preterm infants are less likely to receive important follow up in high-risk infant follow-up clinics and to be referred to and receive services from Early Intervention ,69,70,71There are known racial and ethnic inequities in multiple neurodevelopmental outcomes including ADHD. However, these can be difficult to fully understand because the process of symptom recognition, diagnosis, and treatment along the “ADHD Care Cascade” is complex and represents a myriad of research outcomes to interrogate. Notably, at each step of the “ADHD Care Cascade” where racial and ethnic inequity is identified, it is racism in its many forms that is the root cause. Furthermore, as the “ADHD Care Cascade” is a series of interconnected steps, inequities in one part of the cascade can be propagated, and potentially magnified, at later steps of the “ADHD Care Cascade”. For the purposes of this narrative review, we build on the conceptual framework of Eiraldi et al. and highlight three points along the “ADHD Care Cascade”: (1) symptom recognition, (2) diagnosis, and (3) treatment .The process of entering the “ADHD Care Cascade” and thus being eligible for diagnosis, management, and treatment is contingent on symptom recognition. While there are no genetic or biologic differences between racial and ethnic populations, symptom recognition is racialized and inequities exist, suggesting that racism, in its multiple forms, contributes to inequitable symptom recognition. In a large nationally representative cohort, Cuffe et al. found that Black and Hispanic/Latinx children had a higher prevalence of parent-reported symptoms on the Strength and Difficulties Questionnaire, a valid measure of ADHD ,78. OtheIrrespective of the etiology of higher rates of parental and teacher symptom recognition in Black children, multiple studies have identified that minoritized children are less likely to receive a diagnosis of ADHD. Despite lower rates of symptom recognition, parents of white children are more likely to report that they were told by a healthcare provider that their child has ADHD ,79,81. IThe racial and ethnic inequities in ADHD diagnosis begin as early as five years of age and persist across the pediatric life-course into childhood ,79,83,84It remains unknown why diagnostic inequities exist for minoritized individuals. To begin, diagnostic tools may not have equal validity among different racial and ethnic populations. For example, one study found that the Diagnostic Interview Schedule for Children had differential validity among Black and white children; when seven items with high variation were removed, the diagnostic inequities decreased . HoweverThe lack of a diagnosis often precludes minoritized children with ADHD symptoms and impairments from accessing medically indicated, evidence-based interventions that have a positive impact on educational, social, and lifetime earnings.Once diagnosed with ADHD, there continue to be significant inequities in access to treatments. As noted above, white children are more likely than minoritized children to receive a diagnosis of ADHD. Once diagnosed, white children are also significantly more likely to receive medication than other racial and ethnic groups ,83,88,89When considering the etiology of racial and ethnic inequities in treatment, one must consider the potential of provider biases, both implicit and explicit, that may contribute to inequities in treatment allocation ,91,92,93The inequities in ADHD symptom recognition, diagnosis, and treatment allocation have not been specifically studied in the preterm population. However, we believe that the inequities along the “ADHD Care Cascade” are likely magnified for preterm-born children. We believe that this is likely due to added medical and functional comorbidities that preterm-born children experience as a result of their preterm status, compared to term children, which may make it more difficult to navigate the “ADHD Care Cascade”. Furthermore, the preterm-born population is disproportionately minoritized due to inequities in preterm birth. The intersection of prematurity and race with ADHD likely compound the inequities along the “ADHD Care Cascade”. In other words, the underdiagnoses and undertreatment of minoritized children with ADHD compounds previous inequities in preterm birth, further disadvantaging minoritized children over time. However, further study is needed to fully understand how preterm-born minoritized children traverse the “ADHD Care Cascade”.School readiness at kindergarten entry is associated with long-term academic, economic, and health outcomes . ChildreThere are several mechanisms through which prematurity and ADHD each affect the child’s readiness for school. Neurodevelopmental differences between the term and preterm brain are thought to explain associations between decreasing gestational age and lower teacher assessment of school readiness, kindergarten math and reading scores, and executive function at school entry ,99,100. While prior research has investigated the individual impacts of prematurity and ADHD on kindergarten readiness, less is known about their combined effect. Since school readiness has lifelong consequences, future work should study the extent to which interactions between these two factors affect school readiness and the short- and long-term life-course contribution of school readiness to inequities.ADHD serves as a case study for the long-term impacts of prematurity on childhood neurodevelopmental outcomes across the life-course. The association between prematurity and the development of ADHD has been well documented in the literature, and there is likely a specific phenotype of ADHD in preterm-born children characterized by more symptoms of inattentiveness. ADHD is an important diagnosis to consider among preterm-born children because it is the most common neuropsychiatric diagnosis of childhood and has a significant impact on childhood learning, social interactions, and school achievement. Additionally, it is associated with long-term health, safety, and financial independence. Importantly, treatments for ADHD that improve outcomes are available.However, it must be recognized that the risk of preterm birth is racialized, as are neonatal adverse outcomes. In childhood, racial and ethnic inequities continue to persist, as we highlighted, in (1) symptom recognition, (2) diagnosis, and (3) treatment of ADHD along the “ADHD Care Cascade”. Thus, it is important to recognize not only the long-term life-course impacts of prematurity, but also to specifically address racialized long-term outcomes for preterm-born children.As shown in this narrative review, the repeated and clustered insults of racism, in its multiple forms, which lead to racial and ethnic inequities in the prenatal, perinatal, neonatal, and pediatric period, have significant and compounding impacts on the life-course health and well-being of preterm-born children, including when viewed through the lens of ADHD. Layered onto the impact of premature birth and racial and ethnic health inequity are additional inequities in access, healthcare utilization, economic opportunity, and social capital. Further study must not only investigate the impact of preterm birth on a single outcome, but, instead, consider the life-course impact of preterm birth and the ways in which inequities early in life may change and potentially widen over time. Specifically, researchers must seek to identify strategies to prevent the long-term adverse neurodevelopmental outcomes of preterm-born children while also identifying the modifiable structural and institutional drivers of inequity in neurodevelopmental outcomes over time. The drivers of inequity are repeated and clustered insults across the life-course of minoritized individuals. and along the care cascades they traverse. Thus the effect of these drivers is magnified; widening gaps overtime. As such, creating meaningful interventions to close equity gaps in neurodevelopment are sorely needed and long overdue.


Low birth weight is a key indicator for child health, especially a concern in low-middle-income countries. However, health and medically-related reforms are being actively implemented in some middle-income countries like India. Identifying low birth weight (LBW) babies with their determinants across the whole country is essential to formulate regional and area-specific interventions. The objective of this study was to find out the burden and determinants of LBW on the regional and residential  divisions of India.The present study was based on the NFHS-5 dataset (2019–21), a nationally representative survey in India. A total of 209,223 births were included in this study. A newborn weighing less than 2500 g was considered as LBW. According to the objectives, we used frequency distribution, chi-square test and binary logistic regression analysis for analysing the data.p < 0.001) and its central, northern, and southern regions than those who gave birth in institutions. The study indicates that LBW coexists with lower maternal education levels and poor household wealth index across all regions. About 58% and 57% of cumulative effects of independent variables on LBW can be distinguished in urban and rural India, respectively.About 18.24% of the babies were LBW in India, significantly higher in rural areas than in urban areas (18.58% vs 17.36%). Regionally prevalence was more frequent in western (20.63%) and central (20.16%) rural areas. Regarding maternal concerns, in the eastern and southern regions of India, mothers aged 25–34 were less likely to have LBW children than mothers aged 35–49 years. It was found that the risk of LBW was more likely among the children born out of unintended pregnancies in almost all regions except for eastern part. In rural India, women who delivered children at home were more likely to have LBW children in India (AOR = 1.19, CI: 1.12–1.28, Targeted-specific strategies need to be undertaken as per region and geographical variations. Then only India should be able to decline LBW as proposed by National Health Policy. The birth of a healthy baby signifies an essential benchmark for the survival, health, and nutrition of new-born life. Lower the birth weight, the higher the risk of survival along with the risks associated with the growth and development of a child , 2. The A newborn weighing less than 2500 g is considered low birth weight (LBW) . In 2015The underreporting of births at home and small health clinics may have resulted in the underrating LBW . In 2012The etiology of LBW is known to be multifactorial. Different studies have highlighted several contributing factors for LBW, including genetic, nutritional, demographic, and psychosocial factors, preterm birth, maternal morbidity during pregnancy, care during pregnancy, obstetric complication, antenatal care, multiple pregnancies, etc. , 17, 18.Studies found about 4% decline in LBW from NFHS-3 to NFHS-4 due to a significant improvement of maternal health in India since 2005 by national-level health programs, but no such improvement of LBW was found between NFHS-4 and NFHS-5 , 19–21. The focus of this study is to address the prevailing informational gap region-wise, revealed by the most recent NFHS-5 (2019 – 2021) data. The findings will have tremendous policy implications in terms of the nature of intervention to be carried out in different regions. The present study was carried out to find the burden and determinants of LBW based on India’s regional and residential  divisions.The unit-level data for this study were obtained from a cross-sectional survey designated the National Family Health Survey of 2019–21 (NFHS-5). This NFHS-5 was a national household survey conducted in India by International Institute for Population Sciences (IIPS) that adhered to the DHS's guiding principles by using standardised questionnaires, sample strategies, and field methodology [This study included only Indian women currently residing in India and was of reproductive age (15–49 years). Among the chosen women, children under the age of five were considered for this study. The study excluded women and their children whose sociodemographic or anthropometric data were either missing or incomplete. The sample selection process for the study was shown in the flow chart , if BW < 2500 g was considered as LBW, and if BW ≥ 2500 g was considered normal , 25.These variables were divided into two categories: grouping factors and explanatory factors. The six regional divisions of India based on NFHS have been considered as grouping factors and the entire study has been conducted based on these zonal distinctions. Socioeconomic, demographic, and maternal characteristics were included in the explanatory factors. Most of the explanatory factors were based on prior studies and were available in the NFHS-5 dataset.2). According to the WHO (2004), BMI was classified as underweight if it was < 18.5; normal was considered to be between ≥ 18 and < 25; and overweight was ≥ 25 [The wealth index measured a household's wealth based on the quantity and variety of consumer goods it owns, its assets, and housing characteristics, including its access to drinking water, toilet facilities, and flooring . The diswas ≥ 25 . A woman the WHO 04, BMI wwas ≥ 25 , 29.2) test was used to determine the association between low birth weight and socioeconomic, demographic, and maternal characteristics regarding the urban–rural of residential settings. The variables found to be statistically significant by the χ2-test were included in binary logistic models as independent variables. Independent variables were further examined for multicollinearity issues using the variance inflation factor (VIF), which was considered less than 5. Statistical significance was estimated using a 95% confidence interval (CI), and p ≤ 0.05 was considered significant. The logistic regression model was validated to see if the data fit correctly using the Omnibus Chi-square test [J) was applied to the ROC curve to assess the efficiency of explanatory variables in LBW. It is defined as Youden's J = sensitivity + specificity − 1. Higher J -values in the evaluations would be preferable [The summary of overall India and urban–rural variation of the variables were defined using frequencies and percentages for qualitative data. The differences in the proportional frequency of LBW between urban and rural were analysed using the Z-proportion test. The Chi-square . Additionally, this study estimated that the prevalence of LBW in newborns was more prevalent in western (20.63%) and central (20.16%) rural areas. In contrast, the majority of LBW was comparatively higher in northern (19.20%) and central (18.83%) urban areas  as compared to the urban areas (17.36%) of India  associated with the birth weight, irrespective of their place of residence i.e. urban and rural. Among the sociodemographic factors in urban area, the occurrence of LBW was found to be significantly higher among the Hindus (17.93%), Schedule Caste group (18.74%), 4th or higher birth order (20.53%), pregnancies delivered at home (20.83%), larger families with more than four persons (17.59%) and poor wealth indexed households (21.01%). Contrarily, sociodemographic factors in rural areas were found to have a higher the occurrence of LBW among the other religious groups (21.00%), Schedule castes (19.79%), 1st child (19.56%), home birth deliveries (21.68%), smaller families with less or equal of 4 persons (19.52%) and households under poor wealth index (20.18%).Table rd trimester had a higher prevalence of LBW.The results also show that among the maternal factors in urban areas, the prevalence of LBW was considerably higher among mothers aged 15–24 years (18.11%), unintended pregnancies those were wanted later (21.88%), who had attended up to a primary level of education (20.19%), had not received full ANC (17.93%), had only received ANC during the 2nd trimester (18.28%), was underweight (21.55%), and was anaemic (17.69%). Rural areas have shown an almost similar trend in maternal factors, in contrast to urban areas, unlike the factors such as mothers with no formal education (20.08%) and mother who received ANC in the 3p < 0.05) in all regional divisions, including India. The correct percentage of prediction of the adjusted model for India, Central, East, North, Northeast, South and West in the urban areas 83.38%, 81.48%, 83.84%, 81.83%, 86.96%, 85.96% and 82.49%, while in the rural areas 82.09%, 80.49%, 82.43%, 82.44%, 85.85%, 84.35% and 80.62%, respectively.Tables Tables p < 0.001; AOR = 0.76, CI: 0.70–0.82, p < 0.001) and STs  had a significantly lower risk of LBW than Hindus and General social category, respectively. Furthermore, it appears in the cumulative effect based on AOR that Christians were over four times more likely to suffer from LBW in the urban area of central and western India, while Muslim children were less likely to experience it in the eastern, northern, and western regions, and other religious groups experienced it more likely (over five times) than Hindu children in the southern region. Compared to children from general castes, SCs in east  and OBCs in south  were more likely to be suffered from LBW. The probability of LBW was significantly reduced in the 2nd and 3rd child in urban India including west region, and more or equal of 4th children in the east region based on AOR. In urban western India, children who born at home were more likely to have LBW  than the healthcare institutions. In both unadjusted and adjusted conditions, compared to mothers from the rich wealth indexed family, the lower category (poor and middle class) were more likely to have LBW children in the central, east, north, south and west regions.Concerning the religion and social categories in urban areas of urban India, children in religious Muslims  than 35–49 years. It was found that the risk of LBW was more likely among the unintended pregnancies in almost all regions except for eastern and northeastern part for both COR and AOR. Mother’s educational status was one of the most influential factors for LBW in urban area. Compared to higher educated mothers in central, east, north, south, and west regions of India the lower educated mothers were more likely to have LBW children based on COR and AOR. Also LBW was more prevalent among children whose mothers did not receive full ANC in urban India  and western region . Based on COR and AOR, the prevalence of LBW was also enhanced in the central, eastern, northern, and western regions by receiving the first ANC visit after the 1st trimester. Maternal underweight was found to be a common risk factor for LBW in all regions of India both for COR and AOR, with the highest prevalence occurring in the northeastern region . Anaemic mothers were more likely to have LBW children in the northeast region . The place of delivery and mother’s anemia had significant individual impact on LBW in urban India but became non-significant when adjusted for other variables.Regarding maternal concerns, in the southern regions of India, mothers aged 25–34 were less likely to have LBW children . According to AOR, the prevalence of LBW among the STs was less common in rural India, including central, east, and northeast regions but more prevalent in the west compared to the general caste category. The probability of LBW remained lower among children following the birth of the first child in rural India, including central, eastern, southern, and western regions based on both COR and AOR. The child who born at home were more likely to have LBW in rural India  compare to institutional birth, including central, north, and south regions for both COR and AOR. Family size was a significant factor for LBW; the probability of LBW was lower in households with more than four people in rural India , including central, and eastern regions for both COR and AOR. Mothers from poor families were more likely to have LBW children than rich families in rural India, including central, east, south and west for both COR and AOR.In comparison to Hindu children, Muslims and Christians were more likely to have LBW in the rural central and north regions based on COR and AOR. LBW was more common among the other religious groups in the northern and western regions and also in the overall country , including western regions based on COR and AOR. Unintended pregnancies significantly increased the chances of LBW in east and west India for both COR and AOR. Mothers with lower levels of education were more likely to have LBW children in and across India compared to higher-educated mothers, except for the northeastern region in AOR. The risk of LBW was higher among mothers who did not receive full ANC in overall rural India including central and northern regions based on COR and AOR. In northern region, the risk of LBW was significantly increased when mothers visit for the first ANC after 1st trimester in rural north India both for COR and AOR. LBW more likely found among the underweight mothers in and across rural regions of India both for COR and AOR. Based on COR and AOR, maternal anaemia increase the chances of LBW in rural central India .The LBW children were more likely found among the mothers aged 15–24 years compared to aged 35–49 years in rural India  on LBW because the AUC of predicted probability for the independent variables in each curve was larger than 50%. In the urban area of northeast India, with an AUC value of 67%, and the rural area of west India with an AUC value of 60%, the predicted probability of independent variables had the maximum impact. However, the AUC shows that 58% and 57% cumulative effects of independent variables on LBW can be distinguished in urban and rural India, respectively. Youden’s J indicates there was a minor but discernible impact of the explanatory variables on LBW.The overall effect of the predicted probability of independent variables on LBW, which is vary by region shown in Table Low birth weight remains a public health challenge in LMICs, including India; thus its burden and determinants in different geographic regions need to be known to the stakeholders. The study indicated that although the prevalence of LBW has decreased from the NFHS-3 2005–06) level of 21.5% to 18.24% in the NFHS-5, it has essentially remained stable from NFHS-4 (18.2%) to NFHS-5 , 20, 21.05–06 levSociodemographic and maternal factors were found to be significantly associated with the prevalence of LBW regardless of rural or urban area. In both rural and urban areas, the social category was found to be a significant predictor for LBW, particularly for the Schedule Caste group. The other most common factors for urban and rural areas were pregnancies delivered at home and households with poor wealth index, similar trend has been found from the studies from sub-Saharan Africa, Ethiopia, Sri Lanka, and Bangladesh –37. OtheFurthermore, it seems that in both urban and rural areas, maternal education and ANC become a common factor influencing LBW in the case of maternal variables. The study indicated that lower maternal education had a substantial impact on LBW in both rural and urban areas. Similar findings have shown that lower mother education levels and LBW of children coexist in a number of LMICs, including Ethiopia, Bangladesh, Kenya, Zambia, Pakistan, and Guatemala , 38–40. Regionally, Christians were four times more prone to have LBW in urban central and western India, and other religious groups were almost five times more likely in the Southern region. In contrast, Christians from the South and Muslims from the Central region had higher rates of LBW in rural areas. Therefore, this disparity could be influenced by religious practises, which varies across regions in India. The backward section of contemporary society, including SCs in the eastern, OBCs in the southern urban areas, and STs in the western rural areas, had a disproportionately high risk of having LBW children. Birth order was a significant risk factor that enhanced the incidence of LBW in the northern region. The chance of LBW was more significant for mothers in the western region who delivered at home. Some studies suggested that inappropriate health-seeking behaviour and a lack of access to improved healthcare facilities may indirectly impact a child's birth weight .The current study shows that mothers from low- and middle-income groups in rural and urban areas were more likely to deliver children with LBW. Additionally, the LBW of children was found to be associated with mothers’ anaemia levels and nutritional status (BMI). Underweight mothers were more vulnerable to have LBW in all regions, particularly in urban northeastern regions. Similarly, in urban northeast and rural central region anaemic level of mothers have higher impact on LBW. The availability of public health professionals, infrastructure, modern health care facilities, and public awareness varied by regions in India , 46. ThiThe study has precisely presented the region-wise picture of low birth weight children with its determinants based on the most recent DHS Survey of India, conducted between 2019 and 2021. This provides an opportunity to develop region-specific policies or revise the existing policies to address the age-old problem of LBW in India. The study highlighted regional division because each region has differences based on geographic location, language, culture, climate, ethnicity, and historical context that separate one region from another. The values of AUC and Youden J index indicates that the predicted probability of the selected independent variables on LBW was substantial but low. So, there may be some potential confounders apart from the studied variables which may have effect on LBW. In our next study, we will aim to identify those factors, which could include ecological patterns, epidemiological trends, social norms, values, traditions, and practises. Additionally, if a similar kind of study can be conducted on each state, then state-specific policies can be developed in the country. However, more studies and research needs to be undertaken to understand the holistic picture of various issues particularly associated with low birth weight in India. We did not check the variation of our outcome variable among different regions in India, if the there was a variation, the multilevel logistic regression model was more appropriate. Furthermore, in this study efforts have been made to capture the various factor’s associations and comparisons in different layers of regional divisions. Hence, it paved the way with a substantial contribution towards exploring and understanding varied factors contributing towards the stagnant burden of low birth weight in India.There has been a gradual decline in the burden of LBW in India over a period of time, but there has been hardly any significant decline in its occurrence compared to NFHS-4 data. Thus targeted specific strategies need to be undertaken as per region and residential areas. Approaches should have been region and residential area specific. More emphasize needs to be given on addressing maternal health including nutritional status, improving maternal education and uplifting economic status that was found persistent form NFHS-3 to NFHS-5. Then only India should be able to reduce LBW as desired, which has also been emphasised by National Health Policy. The present study will promote the nation in achieving five of the United Nations’ seventeen Sustainable Development Goals: no poverty, zero hunger, good health and well-being, quality education, and reduced inequalities. A trend analysis is required as it appears that the LBW issue in the country has almost stagnated over the last 5 years.


Polygenic scores (PGS) for attention‐deficit/hyperactivity disorder (ADHD) negatively predicts educational attainment (EA), but it remains unclear how ADHD symptoms, PGS for EA, and shared familiar factors influence the associations between PGS for ADHD and school performance.We combined survey data on ADHD symptoms, PGS, and register‐based, objective measures of compulsory school performance at age 16 for 6049 twins in the Child and Adolescent Twin Study in Sweden. Linear and instrumental variable (IV) regression models were used to estimate the association between PGS for ADHD and grade point average (GPA), overall and by natural science, humanities, and practically oriented  subject categories. The models were adjusted for parent‐rated ADHD symptoms, PGS for EA, and shared familial factors (dizygotic twin comparisons) to examine how these factors influenced the associations between PGS for ADHD and school performance.β = −0.12, 95% confidence interval =  for overall GPA with minor differences by subject category. Adjustment for ADHD symptoms attenuated these associations to a small degree compared to PGS for EA, and shared familial factors respectively. Stronger associations were observed using IV regressions compared to linear regression. However, in the IV regression analyses, most associations between PGS for ADHD and GPA in the practically oriented subject category were not significant.PGS for ADHD were negatively associated with school performance; Associations between PGS for ADHD and school performance are to a small degree influenced by ADHD symptoms, compared to PGS for EA and shared familial factors. These results highlight important considerations for research using PGS for ADHD to control for genetic factors, and for future clinical applications aiming to determine genetic liability towards ADHD. Polygenic scores for ADHD are negatively associated with a broad range of educational outcomes.The association between polygenic scores for ADHD and school performance is to a small degree explained by phenotypic ADHD symptoms.Polygenic scores for educational attainment and, in particular, shared familial factors are of high importance in the association between polygenic scores for ADHD and school performance.The weak influence of phenotypic ADHD symptoms on these associations highlight important considerations in research and clinical applications regarding the specificity of polygenic scores for ADHD.Attention‐deficit/hyperactivity disorder (ADHD) is characterized by impairing and developmentally age‐inappropriate inattentive and hyperactive behaviors  , linkage disequillibrium , and environmental or diagnostic mechanisms   and IV analyses with two different PGS for ADHD .We extracted data on 6049 twins from the Child and Adolescent Twin Study in Sweden (CATSS) that have been genotyped. Parents of participants in CATSS were interviewed via telephone regarding behavior, development, and other characteristics at ages 9 or 12 years . Of these, 248 samples identified as non‐European were excluded as the discovery GWAS were based on European samples. Non‐genotyped twins in monozygotic pairs had their genotype inferred from their genotyped co‐twin. Details of genotyping procedure, quality control, imputation, and principal component analysis (PCA) have been published elsewhere    on the overlapping SNPs using 1000 Genomes Project European samples as LD‐reference. PGS were calculated for each trait, including SNPs based on seven p‐value thresholds  using PLINK. Finally, we ran a PCA on these PGS within each trait to derive a PGS based on the first principal component. A recent paper has shown that this approach can incorporate the majority of polygenic variability in the PGS , overall, and in three different subject categories defined based on their content: natural science , humanities/language , and practically oriented  subjects. See Appendix Sex at birth was determined from the Total Population Register . Compulsory school graduation year (2008–2013) was determined from the NSR and coded as a continuous variable (0−5).We addressed our aims using both ordinary and IV analyses, and applied these to all school performance measures.We estimated a crude association between ADHD‐PGS and school performance using LR. The associations were adjusted for sex, the linear effect of compulsory school graduation year, and five PC's were included to control for potential population stratification .Next, we adjusted these associations for ADHD symptoms, EA‐PGS, ADHD symptoms and EA‐PGS jointly, and shared familial factors in separate models. A family fixed effects approach  was used to adjust associations for shared familial factors where each twin pair is treated as a separate stratum, thereby removing influences from factors shared between twins from the same family  on the association between ADHD‐PGS and school performance (see Appendix 1‐SP and e2‐SP) on the association with school performance as the IV estimate only relies on the PGS mutual dependence on the polygenic load. Key IV assumptions are first that the different PGS for ADHD correlate significantly with each other . We used two‐stage least squares regression was used for estimation; first regressing the ADHD‐PGS on the ADHS‐PGS, then regressing the outcome on the predictions of ADHD‐PGS, including any covariates at both stages. The necessary assumptions were evaluated by the first stage results, rejection of null hypothesis Cov = 0, and while the second assumption is untestable, we replicated previous associations between ADHD‐PGS and phenotypic ADHD symptoms and a clinical diagnosis of ADHD  of twins were dizygotic, with a slightly higher proportion of females among monozygotic twins, 53% versus 47%. Rates of missingness were low (<1%) in GPA and individual subjects  SD lower GPA. The association between the ADHD‐PGS and overall GPA decreased to β = −0.10  when adjusting for ADHD symptoms, and to β = −0.07  when adjusting for EA‐PGS. Joint adjustment for ADHD symptoms and the EA‐PGS in the same model had no marked influence on the associations. When comparing twins from the same family, the associations dropped to β = −0.04  (Table Rows labeled “LR” in Table 2) Table .β = 0.06; p < 0.001; F‐statistic = 15.6), and after adjusting for phenotypic ADHD symptoms, and EA‐PGS, but not when adjusting for shared familial factors . Compared to the LR analyses, adjustment for ADHD symptoms, EA‐PGS, and shared familial factors influenced the associations similarly in relative terms , these findings should be verified by other studies.We found that adjustment for shared familial factors attenuated the associations between ADHD‐PGS and school performance by about 67%, suggesting a stronger influence compared to previous research on 2366 twin pairs  of variation in test results (age 16)   with small differences between responders and non‐responders in terms of variables such as socioeconomic status . However, we have emphasized general tendencies, rather than outcomes from significance testing. Future studies using larger samples are needed to confirm our findings. While register‐based measurements of school performance has advantages compared to survey based measures , we acknowledged that these benefits do not circumvent biases in how teachers grade students  that may affect our estimates, in particular when adjusting for phenotypic ADHD symptoms. We also acknowledge that more recent methods to calculate PGS   than others. Overall, these associations are influenced to a small extent by phenotypic ADHD symptoms, to a greater degree by PGS for EA, while shared familial factors show the strongest influence.Advances; Pearson ; Henrik Larsson has served as a speaker for Evolan Pharma and Takeda/Shire, and has received research grants from Takeda/Shire, all outside the submitted work. He is Editor‐in‐Chief for JCPP Advances. Andreas Jangmo has served as a speaker for Takeda. Cynthia M. Bulik reports: Shire/Takeda  and is on the Editorial Advisory Board for JCPP Informed consent for participation in CATSS was obtained from parents, and ethical approval was obtained from the Regional Ethics Board in Stockholm.Andreas Jangmo: Manuscript, original draft and review/editing, formal analysis, methodology, visualization. Isabell Brikell: Manuscript, original draft and review/editing. Ralf Kuja‐Halkola: Manuscript, original draft and review/editing. Inna Feldman: Manuscript, original draft and review/editing. Sebastian Lundström: Manuscript, original draft and review/editing. Catarina Almqvist: Manuscript, original draft and review/editing. Cynthia M. Bulik: Manuscript, original draft and review/editing. Henrik Larsson: Manuscript, original draft and review/editing, conceptualization, funding acquisition, supervision.Supporting Information 1Click here for additional data file.