Objectives: Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present post hoc psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions.Methods: The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6–12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated post hoc included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity ; responsiveness to changes in assessments of ADHD severity ; and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups.Results: Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo . The CGSQ demonstrated strong internal consistency  and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as −9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9% p = 0.003).Conclusions: CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388. It was originally developed to measure the strain experienced by caregivers of children with serious emotional and behavioral problems over a previous 6-month period. It was validated initially in a sample of caregivers of children with parents in the military who needed mental health services, with a reported internal consistency  of 0.93 . DR/ER-MPH (formerly HLD200) is an evening-dosed ADHD medication designed to delay the initial release of MPH by ∼8 to 10 hours to provide onset of treatment effect upon awakening, lasting into the evening  that assessed the effects of DR/ER-MPH on caregiver strain, as measured by the CGSQ ; ADHD Rating Scale-IV (ADHD-RS-IV) score ≥90th percentile for age and gender, and ≥26, at baseline; Clinical Global Impression—Severity (CGI-S) score ≥4 and Conners' Global Index—Parent (CGI-P) score >10 at baseline; at least a partial clinical response to MPH by judgment of the investigator; and early morning functional impairment and/or difficulties performing a morning routine of ≥30 minutes between 6:00 AM and 9:00 AM. Key exclusion criteria included the following: history of or current medical condition or laboratory result that could either jeopardize participant safety or interfere with study participation; history of psychosis, bipolar disorder, anorexia nervosa, bulimia, or suicide attempt; current depression, anxiety, conduct disorder, substance use disorder, or other psychiatric conditions; history of severe allergic reaction or intolerance to MPH; and past use of psychotropic medications, including antidepressants, mood stabilizers, and antipsychotics (with the exception of stimulants and nonstimulants for the treatment of ADHD).Male and female children aged 6–12 years with ADHD were enrolled if they met the predefined study inclusion and exclusion criteria. Key inclusion criteria included the following: a diagnosis of ADHD based on the The study was conducted in two phases: a screening/washout phase lasting up to 2 weeks (washout of ≥72 hours before randomization), and a 3-week, randomized, placebo-controlled phase utilizing a forced-dose titration schedule. At the start of the treatment phase, participants were randomized in a 1:1 ratio to receive either DR/ER-MPH or placebo once daily each evening for 3 weeks. Dosing was initiated at 40 mg/day each evening at 8:00 PM (±30 minutes) for 1 week, with scheduled titration, as tolerated, over the subsequent 2 weeks to 60 and 80 mg/day. The maximum allowable dose was 3.7 mg/kg/day and a 20-mg decrement was permitted for safety or tolerability reasons. Participants unable to tolerate at least 40 mg/day during the final week were discontinued. Participants were also permitted to adjust the evening dosing time between 6:30 PM and 9:30 PM in 30- or 60-minute increments per week to achieve optimal morning control of observed ADHD symptoms.As previously reported . The ADHD-RS-IV measures severity of ADHD symptoms, with 18 items rated on a 4-point scale from 0 (reflecting no symptoms) to 3 (reflecting severe symptoms), and total possible scores ranging from 0 to 54 . Psychometric analyses used ADHD-RS-IV data from screening and week 3. Ratings on the ADHD-RS-IV were also obtained specifically from 6:00 AM to 9:00 AM (ADHD-AM-RS). Psychometric analyses used ADHD-AM-RS data rated over the previous week from baseline (randomization) and week 3. Higher scores indicate greater symptom severity.The CGI-P is a 10-item caregiver-completed rating scale designed to assess features of general psychological difficulty that may be expressed behaviorally, academically, socially, or emotionally in children and adolescents aged 6 to 18 years (Conners 1989). It consists of two subscales: restless-impulsive and emotional lability. Each item is rated on a 4-point scale, with 0 denoting “never/seldom” and 3 denoting “very often/frequently.” Psychometric analyses used CGI-P data from screening, which assessed the previous month, and week 3 assessing the previous week. Reductions in CGI-P scores indicate an improvement.Finally, the CGI-S and CGI-I are clinician-rated global scales that provide assessment of severity (CGI-S) and its change from baseline (CGI-I). For the psychometric analyses, the CGI-S scores from screening were used. It is rated on a 7-point scale from 1  to 7 (“extremely ill”). The CGI-I was administered at week 3 and is also rated on a 7-point scale from 1 denoting “very much improved” to 7 denoting “very much worse” (Guy 1976). Scores below the midpoint indicate improvement and scores above the midpoint indicate worsening.All analyses were performed on the intention-to-treat (ITT) population, defined as all randomized participants who received at least one dose of study drug and had at least one postbaseline evaluation on the ADHD-RS-IV. The effect of DR/ER-MPH treatment on the CGSQ compared with placebo was assessed at week 3 using a prespecified analysis of covariance model with treatment as the main effect, and study center and baseline score as the covariates.post hoc psychometric analyses were conducted as part of the validation process for the CGSQ as a measurement of caregiver strain. Internal consistency for caregivers of children with ADHD was evaluated at screening using Spearman correlations and Cronbach's alpha. Spearman correlations of each item with the total score, omitting that item, were calculated. A threshold of 0.30 (Stevens 1951) was used to evaluate the Spearman correlations. Cronbach's alpha values were calculated for all items and after each item was deleted.The Test/retest reliability was evaluated using intraclass correlation coefficients (ICCs) between CGSQ total scores at screening and week 3. Test/retest reliability is the degree to which scores on a scale are consistent when an individual is evaluated under the same conditions, but on different occasions. Ideally, every variable needs to be kept the same, so that the scale can only reflect the construct it is designed to measure . Convergent and divergent validity refers to the extent to which a measure relates to other measures or variables based on theoretical content, or the expected relationship with the variable(s) chosen. The CGSQ was expected to be correlated with both the ADHD-RS-IV and ADHD-AM-RS because the strain on the caregiver is presumed to be related to the severity of the ADHD symptoms  and among participants categorized into predefined ADHD-RS-IV change categories . Statistical significance was determined using ANOVAs with tests for linear trend to determine if mean changes in scores were different between groups.Anchor-based estimates of meaningful change (meaningful change threshold [MCT]) for the CGSQ were identified to help interpret CGSQ total scores by providing responder definitions. Receiver operating characteristic curves were used to estimate MCTs by identifying the CGSQ score changes that best discriminated those simultaneously reaching two well-accepted response criteria (≥30% decrease in ADHD-RS-IV and patients categorized into CGI-I of 1 or 2) from those who do not (<30% decrease and CGI-I >2). A mean MCT, based on the responder definitions anchored to ADHD-RS-IV and CGI-I, was calculated and used as a responder definition to compare response (the proportion of patients reaching the responder definition) between DR/ER-MPH and placebo treatment groups using chi-square statistics.n = 81; placebo, n = 80). Demographics and baseline characteristics of the study population have been described in detail elsewhere and were comparable between treatment groups . When evaluated by randomized groups, mean CGSQ scores at screening were comparable between DR/ER-MPH and placebo.After 3 weeks of treatment, caregivers of children treated with DR/ER-MPH reported significantly lower strain compared with caregivers of children who received placebo, as measured by CGSQ total scores  had no statistically significant change in mean (standard deviation) ADHD-RS-IV scores from screening (30.1 [10.4]) to week 3 (38.9 [11.4]).Internal consistency of the CGSQ at screening was strong . Cronbach's alpha remained the same when each item was deleted, and each item-total correlation was above the threshold of 0.30 (Stevens 1951), suggesting that all items contribute equally to the measure . The CGSp < 0.05) as well as ADHD-RS-IV (p < 0.0001) and CGI-P (p < 0.0001) scores. Mean CGSQ total scores were also progressively higher (worse) as ADHD severity worsened , with significant linear trends  than with ADHD-AM-RS  confirming convergent and divergent validity of the CGSQ  across ADHD-RS-IV change categories, suggesting that improvements in ADHD-RS-IV scores are reliably related to improvements in CGSQ total scores (p < 0.0001) between changes in CGSQ total scores with changes in ADHD-RS-IV, ADHD-AM-RS, and CGI-P scores from screening to week 3 (baseline to week 3 for ADHD-AM-RS) as well as with CGI-I absolute scores at week 3 (p < 0.0001). Greater improvement reported in CGI-I ratings was also associated with greater improvements (reductions) in CGSQ total scores , and CGI-I of 1 or 2 (−12). On using this MCT estimate as a responder definition, the proportion of participants with a meaningful change was significantly greater among the DR/ER-MPH treatment group versus placebo  morning and evening subscales  been used. The trial was not primarily designed to assess the test/retest reliability of the CGSQ, and the interval of 3 weeks between the two CGSQ assessments was slightly longer than the 2-week interval that is most often recommended (Streiner et al. The results should also be considered in light of limitations of the study design discussed previously (Pliszka et al. Post hoc psychometric analyses found the CGSQ to have strong internal consistency, good test/retest reliability, known groups validity, convergent and divergent validity, and sensitivity to change among caregivers of children aged 6 to 12 years with ADHD. An MCT of −9.0 was estimated for the CGSQ. The proportion of participants receiving DR/ER-MPH who achieved this MCT for the CGSQ was significantly greater than participants receiving placebo.Caregivers of children with ADHD reported significant reductions in caregiver strain after 3 weeks of treatment with DR/ER-MPH versus placebo, as measured by the CGSQ. Several studies have described the considerable burden associated with caring for children with ADHD, even when they are receiving pharmacological treatment. Improvements in caregiver strain with 3 weeks of DR/ER-MPH treatment is likely related to the extended duration of effect of DR/ER-MPH, which provides control of ADHD symptoms from the early morning through to the evening, typically the times when the majority of family interactions occur. The CGSQ was shown to be a valid and reliable instrument for assessing caregiver strain, and may be helpful in clinical practice to optimize treatment outcomes that may affect the whole family.


Attention deficit hyperactivity disorder (ADHD) is a pervasive condition affecting persons across all age groups, although it is primarily diagnosed in children. This neurological condition affects behavior, learning, and social adjustment and requires specific symptomatic criteria to be fulfilled for diagnosis. ADHD may be treated with a combination of psychological or psychiatric therapeutic interventions, but it often goes unattended. People with ADHD face societal bias challenges that impact how they manage the disorder and how they view themselves. This paper summarizes the present state of understanding of this disorder, with particular attention to early diagnosis and innovative therapeutic intervention. Contemporary understanding of the mind–brain duality allows for innovative therapeutic interventions based on neurological stimulation. This paper introduces the concept of neurostimulation as a therapeutic intervention for ADHD and poses the question of the relationship between patient adherence to self-administered therapy and the aesthetic design features of the neurostimulation device. By fabricating devices that go beyond safety and efficacy to embrace the aesthetic preferences of the patient, it is proposed that there will be improvements in patient adherence to a device intended to address ADHD. Attention deficit hyperactivity disorder (ADHD) is a neuropsychiatric disorder present in as much as 5% of the population . AccordiADHD is a neuropsychiatric disorder known to be highly heritable and linked to a variety of genetic factors that affect neurological and molecular systems . EpigeneAdhesion G Protein-Coupled Receptor L3 (ADGRL3) (previously known as LPHN3) is a gene associated with ADHD in a large sample of children and adults . ADGRL3 A central theory in the pathophysiological causes of ADHD is rooted in delays of the reward system in executive functions, leading to a reduction in control and inhibitory deficits . The exePrenatal exposure to chemicals  in the environment has also been shown to increase the risk of having the disorder. Antiepileptic drugs, such as valproate, an anticonvulsant and mood-stabilizing drug for the treatment of seizures and manic episodes associated with bipolar disorder, and carbamazepine, an anticonvulsant, are used to treat neurological disorders, but their use in pregnant mothers heightens the risk of congenital neurodevelopmental problems in their children ,22. A DaThe three subtypes of ADHD currently recognized are predominantly inattentive (IA); predominantly hyperactive-impulsive (HI); and the “combined” type, a blend of the other two, which is the most common . CliniciThese associated symptoms disrupt the academic and social aspects of a patient’s life. ADHD symptoms related to behavior can greatly hinder the social abilities of patients, making it harder to grasp social cues, which could pose difficulty in forming friendships with peers. Patients with HI ADHD may engage in spontaneous and risky behavior that can make them a danger to themselves . The thrAdditionally, ADHD is associated with sleep problems including insomnia, reduced sleep duration, and issues affecting circadian rhythms . Some reA further characteristic of ADHD pertains to the self-defeating behavior known as emotional dysregulation . This beADHD is most commonly diagnosed in children and adolescents (ages 5–17). Many other rating systems exist for ADHD. One example is the National Institute for Children’s Health Quality (NICHQ) Vanderbilt Assessment scale which is much longer than the ADHD-RS-V. The NICHQ assessment consists of 55 questions for the parent form and 43 questions for the teacher form that cover both symptoms and performance . The SwaIn addition to these symptom-based tests, a technological method of diagnosis exists that employs electroencephalography (EEG). The FDA approved the Neuropsychiatric EEG-Based Assessment Aid (NEBA) system for supporting a clinical ADHD diagnosis in 2013 . As per Given the genetic basis of the etiology of ADHD , the proWith the diagnosis of ADHD, many patients stand at a greater risk of suffering from other accompanying mental disorders, such as depression or dysthymia (persistent mild depression). Approximately 16% to 37% of patients diagnosed have comorbid major depressive disorder/dysthymia, putting them at a much higher risk of suicidal behavior . GrowingMany persons with ADHD do not seek proper treatment, as several mental health disorders carry a negative stigma that impedes the pathway to therapy. In recent studies, around 25% of parents did not want “their child to make friends with a child with ADHD” with some even disregarding the possibility of the presence of a disorder and blaming the child’s family for their inability to raise a child properly . SimilarClinical management follows three broad paths: behavior adjustment and accommodations, medication, and a combination of both. The standard of care for patients with ADHD varies with age and manifest intensity of the condition. However, according to the National Institute for Health and Care Excellence (NICE) standards, before medication, lifestyle should be the initial focus for adjustments . This inFinding the best-fit medication for a patient is usually carried out through trial and dose adjustments, paying careful attention to contraindications, attenuation of symptoms, or the emergence of comorbidities. Additionally, classified as treatment-emergent adverse effects, standard stimulant symptoms for methylphenidates and amphetamines most often include a combination of the following: insomnia, diminished appetite, headaches, nausea, or gastrointestinal pain. . The folMethylphenidate is a first-line drug in the treatment of ADHD. It stimulates the central nervous system (CNS) by affecting the bioavailability of chemicals in the brain and nerves, such as dopamine and norepinephrine, that contribute to hyperactivity and impulse control. Often taken orally, but sometimes delivered transdermally, it is sold under brand names such as Ritalin, Metadate ER, Concerta, and Methylin.Atomoxetine is a first line drug in the treatment of ADHD. It is a norepinephrine reuptake inhibitor and is a non-stimulating drug believed to work by increasing norepinephrine and dopamine levels in the brain. It is taken orally and may be used with a stimulant. It is sold under the brand name Strattera with generics produced by APOTEX, USA, and Teva Pharma, USA. Specific treatment-emergent adverse effects for atomoxetine include headaches, dry mouth, dizziness, appetite changes, and gastrointestinal issues such as nausea, vomiting, constipation, and abdominal pain. [al pain. .Dexamphetamine is used in the treatment of ADHD. It is an amphetamine that stimulates through the inhibition of the transporter proteins responsive to the monoamine neurotransmitters serotonin, norepinephrine, and dopamine. It is taken orally and is sold under the brand names Dexedrine Spansule, ProCentra, and Zenzedi.The implementation of stimulant medication as an ADHD treatment has been the standard in clinical settings. The stigma that children’s early usage of controlled substances could pose issues with substance abuse disorders later in life has been researched. Parents have concerns because stimulants, such as methylphenidate, amphetamine, and opioids, can both increase dopamine release, so their concurrent use can reinforce dopamine signals and increase abuse risk . HoweverThrough guidance made possible under the Individuals with Disabilities Education Act (IDEA), schools serve as a major resource in the management of patients with ADHD. The diagnosing physician will often refer to proper psychotherapy and pharmacological routes depending on the severity of the patient’s case, which may include accommodations at school . The locWith anywhere from 40% to 80% of diagnosed children having this condition continue into their adolescent development, ADHD symptoms are not eliminated entirely as the patient ages . Its conNeurofeedback treatment is an alternative to medication enabled through the use of an EEG and brain wave training . During The anthroposophical therapy of Rudolf Steiner (1861–1925) and Ita Wegman (1876–1943) has been applied to ADHD and has received mixed reviews, specifically for weakness in complying with the tenets of evidence-based medicine . This hoADHD is proven to have adverse effects on patients, including hyperactivity, inattentiveness, learning disabilities, emotional imbalance, and depression or anxiety . In addiAmong people who have been diagnosed with ADHD, there are discrepancies in how they are viewed by society based on their age and sexual identity, the status of their medical treatment, and their economic standings ,83,84. WDespite the stereotypes and arguably unethical claims that society associates with this condition, there are some incredibly positive characteristics that researchers have discovered in individuals with ADHD. In fact, author Dale Archer emphasizes how patients diagnosed with ADHD are often highly successful entrepreneurs . Some inImproved understanding in the molecular etiology of ADHD has created opportunities for technological interventions based on neurostimulation. Neurostimulation is the purposeful modulation of the nervous system’s activity using invasive  and non-invasive  or transcranial electric stimulation, tES, such as transcranial direct current stimulation (tDCS) and transcranial alternating current stimulation (tACS)). The success of neurostimulation can likely be attributed to the “electroceutical theory” of neurostimulation and the “augmentation theory” of neurostimulation. Electroceuticals are nascently produced biochemicals whose levels are potentiated under the influence of the applied electric field . The upw3 in size, and an H-coil can target structures that are up to 6 cm deep [The techniques of neurostimulation vary widely, reflecting the diverse possible clinical indications. However, studying this treatment and its direct effects is a challenge due to the inability to eliminate confounding factors such as brain maturation and working with a population that is overall forgetful of tasks and defiant . Dependi cm deep . Additio cm deep . The usa cm deep .Transcranial direct stimulation (tDS), also known as transcranial DCS (tDCS), uses multiple externally placed electrodes and direct electric current of 0.5 to 2 mA to the targeted regions of the brain between the negative cathode and positive anode on the scalp . In FiguAnother promising method of neurostimulation for ADHD treatment is Trigeminal Nerve Stimulation (TNS) which employs either external electrodes and an external, on-body pulse generator (eTNS) or subcutaneously implanted electrodes and an accompanying implantable pulse generator (sTNS) that delivers pulses to the trigeminal nerve and can be programmed to specific charges, frequencies, and time periods for each patient . The sen® eTNS® System. The device consists of the main component that generates pulses to stimulate the trigeminal nerve and an electrode array accessory to deliver the pulses [® is battery-operated, rechargeable, and involves minimal steps to assemble and use. The kit is sold for around USD 1000, with enough disposable electrode pads for 4 weeks, and additional electrode pads sold for USD 70. The device is worn on the forehead, and treatment occurs when the patient is asleep, so their daily habits are minimally disrupted. However, this may not be ideal for patients with sleep disorders or those whose sleep is accompanied by abnormal movements and physical behaviors, who could peel off the electrodes or otherwise disrupt the system throughout the night. The device does not have a timer, so the patient must sleep for the exact duration of treatment, although no side effects are listed for longer stimulations. This device is designed for children over the age of 7 and cannot be used for any patients with cardiac implants or any other body-worn electronic devices, such as insulin pumps. The instructions are specific, as the pads cannot be placed anywhere on the body besides the forehead and cannot be used in the presence of radio frequency energy, such as that of a television, cell phones, or microwaves due to the radio frequency used by the machine. These guidelines may lead to compliance failure, especially in the pediatric and hyperactive audiences that may find keeping track of these specifics to be complicated. Additionally, the Monarch® requires the patient to set the desired current, so a parent or caregiver plays a heavy role in ensuring the treatment is delivered safely and effectively. The device includes a lock button and an optional input passcode so caregivers can ensure that the patient is not altering the settings without permission. Clinicians need to be familiar with the patient’s family, routine, and domestic life before prescribing, because inadequate oversight may render the treatment ineffective or potentially dangerous for young patients. NeuroSigma® conducted a double-blind, randomized study with 56 children, 30 active participants, and 26 sham participants between the ages of 8 and 12 years old. The patients were diagnosed with the ADHD-RS-IV scale, comprised of 18 questions about the child’s behavior in the past month completed by a parent or guardian [® believes this treatment could fill a gap in ADHD treatment and provide safe and longer-lasting treatment. Further studies should investigate the underlying mechanisms of the treatment, provide an explanation for the decline in ADHD-RS scores following treatment, and thoroughly assess any blood pressure or heart rate effects that could be caused by stimulation of the trigeminal nerve.Several companies are targeting this avenue of ADHD therapy to create portable neurostimulation devices for in-clinic and at-home therapy. NeuroSigma was the first to receive FDA clearance, using the de novo premarket review pathway, for their neurostimulation device for pediatric ADHD, called The Monarche pulses . It operguardian . This suguardian . The sidguardian . Among r®, their device, called the AF-RNS®, is worn as a cap but has a unique machine-learning capability [®, this device is worn during the day and involves parallel cognitive training tasks.Other companies, such as Innosphere, have similar products under clinical trial in Europe. Similar to The Monarchpability . TreatmeAn alternative to the above methods is known as cognitive behavioral therapy (CBT). This method consists of psychoeducation, boosting the motivation of the patient, and traditional organization/planning and adaptive thinking training . CBT sesThere is considerable potential for electrostimulation devices to move to at-home care and join the growing family of the Internet of things (IOT) with an intersection with digital or remote health. This provokes consideration of the relationship between aesthetics, as an element of biomedical device design, and in-home adherence to therapy using devices to address ADHD. Research surrounding color perception in ADHD patients is noteworthy. A study comparing the success of individuals with and without ADHD in rapid color identification tests concludes that ADHD patients are more likely to make errors and take longer in tasks that involve quickly identifying and naming color, especially on the blue-yellow color axis . The perADHD is a complex disorder that must be fully understood to avoid passing unwarranted judgment on people for things out of their control and allow those individuals equal opportunities for success in their education and workplace. As new treatment options are being developed, patients are better able to manage and understand their symptoms. However, patient adherence to these new treatments is crucial, and with the current understanding of the symptoms of this diagnosis, this presents a challenge in itself. While great strides have been made in identifying genetic factors, research is still being conducted to discover all the factors, including environmental factors, that influence the etiology and progression of the condition. As ADHD awareness increases, many preconceived notions are being reevaluated, allowing for these patients to more comfortably seek treatment and discuss their symptoms with their friends and families.In order to further develop neurostimulation as a widely accepted therapy, large clinical trials are needed to delineate the attributes of neurostimulation that address symptoms of ADHD. Studies that aim at the underlying mechanisms of action for electrostimulation devices used in ADHD therapy are necessary to gain public approval for this treatment. With this information, the use of neurostimulation technologies is likely to receive growing attention, mainly towards the unique modulation attributes of frequencies, duty cycle, and duration that are needed to address the classes of symptoms associated with ADHD. There is likely to be rapid migration from the clinic to at-home therapy supported by the Internet of Medical Things (IoMT) and remote health monitoring. The attendant challenge of patient adherence to therapy will necessitate design considerations to promote patient adherence. This includes ergonomic and aesthetic design considerations. Another hurdle presented is increasing the proportion of these patients that receive treatment and ensuring that this technology is convenient and affordable. A non-critical treatment may not be covered by all insurances, further disadvantaging demographics that cannot afford advanced treatments. By increasing the societal awareness of the complexities of ADHD and fighting negative stigma through research and education, more ADHD patients may come to terms with their struggles and seek treatment.


In utero exposure to household air pollution (HAP) from polluting cooking fuels has been linked to adverse pregnancy outcomes including low birthweight (LBW). No previous study in Uganda has attempted to investigate the association between the different types of biomass cooking fuels and LBW. This study was conducted to investigate the association between wood and other biomass cooking fuel use with increased risk of LBW, using the 2016 Uganda Demographic and Health Survey for 15,270 live births within five years prior to interview. LBW, defined as birthweight of <2500 g, was estimated from maternal recall and health cards. Association between household exposure to the different solid biomass cooking fuels and LBW was determined using multivariable logistic regression. Biomass cooking fuels were used in 99.6% of the households, with few (0.3%) using cleaner fuels and 0.1% with no cooking, while the prevalence of LBW was 9.6% of all live-births. Although the crude analysis suggested an association between wood fuel use and LBW compared to other biomass and kerosene fuel use , after adjusting for socio-demographic and obstetric factors, no association was observed . LBW was significantly more likely among female neonates (AOR: 1.32 (95% CI: 1.13–1.55) and neonates born to mothers living in larger households . LBW was significantly less likely among neonates delivered at term , born to women with secondary or tertiary level of education , living in households with a higher wealth index , Eastern  and Northern  regions. The study findings suggest inconclusive evidence regarding the association between the use of wood compared to other biomass and kerosene cooking fuels and risk of LBW. Given the close observed association between socioeconomic status and LBW, the Ugandan government should prioritize public health actions which support female education and broader sustainable development to improve household living standards in this setting. Globally, about 2.8 billion (36%) people rely on kerosene and biomass fuels , referred to collectively as biomass fuels, for cooking and heating ,2. In AsGlobally, exposure to HAP results in approximately four million deaths annually, 4.8% of all disability-adjusted life years, and 7.7% of global mortality , and is Women and children under five years of age are more vulnerable to the adverse effects of HAP, due to gender-patterned cooking roles which lead to greater HAP exposure among females, while children aged under five years are often kept in close proximity to their mothers during cooking periods . ExposurStudies and meta-analyses have identified an association between exposure to biomass compared to cleaner fuels  with increased risk of LBW ,7,11,12.Our study was conducted in Uganda, a low-income country in Sub-Saharan Africa , where 9The low proportion of households using cleaner fuels, corresponding high use of wood fuel, and relatively high utility of switching from raw to processed biomass fuels  suggests the need to investigate the relative risk of LBW if households used other biomass fuels rather than wood. The aim of this study was therefore to determine the association between the use of wood compared to other types of biomass and kerosene cooking fuels and the risk of LBW in Uganda, using the population-based 2016 Uganda Demographic and Health Survey (UDHS).The UDHS (2016) is a cross-sectional population-based national dataset funded by the U.S. Agency for International Development, with the birth recode  and relevant variables from the individual recode being extracted for this study . The birSingleton live births, occurring at term (≥37 weeks gestation) and/or pre-term (<37 weeks gestation) which occurred in the last five years (2012–2016) from the time of interview were included in the study. Multiple births were excluded from the analysis because of the high risk of LBW among multiple pregnancies .The wealth index provided by DHS is calculated through principal component analysis (PCA), including assets, toilet facility, drinking water sources, cooking fuel, and house construction as predictor variables , with thSelf-reported main household cooking fuel was categorized into cleaner fuels (LPG), electricity, biogas, and no cooking), and biomass and kerosene fuels . Households, where cooking was not done, were classified as using cleaner fuel because it was assumed that HAP levels in these households would be comparable to households that used cleaner fuels. The exposure variable was the biomass or kerosene cooking fuels, categorized into wood and other biomass and kerosene fuels .The outcome variable was LBW defined as a birthweight of less than 2500 g, obtained from either the health card (34%) or the maternal recall of child’s weight at birth (66%).2). Circumstantial pregnancy-related covariates included mode of delivery , the timing of first antenatal care visit (ANC) (≤5 or >5 months), number of ANC visits (≥4 or <4), sulphadoxine-pyrimethamine (SP) (yes or no), birth interval (<24 months or ≥24 months), iron-folate supplementation (yes or no), deworming during pregnancy (yes or no), birth interval, based on WHO categorization, of less than 24 months or birth intervals of ≥24 months was used [2, was categorized as low when BMI was <18.5 or normal when BMI was ≥18.5 [Covariates were identified from the literature ,36,37,38was used . BMI, meas ≥18.5 , as theras ≥18.5 ,43.p-values were reported. Clinically relevant variables, those with a p-value was less than 0.2, and variables without high levels of missing, in the bivariate analyses were included in the multivariate logistic regression model. Missing values were handled by case-wise deletion.Categorical variables were summarized using frequencies and proportions. Skewed continuous variables were summarized using the median and inter-quartile range (IQR), while normally distributed continuous variables were summarized using means and standard deviations. Bivariate and multivariate logistic regression, using survey commands to adjust for the complex sampling structure, was deployed to determine the association between exposure to wood and other forms of polluting fuels and LBW. The odds ratios (OR), 95% confidence intervals (95% CI), and Sensitivity analyses were undertaken to ensure robustness of study findings and to further investigate confounding factors  that could not be accounted for in the main analysis due to a large proportion of missing data . FurtherUSAID obtained ethical approvals from the relevant authorities in Uganda to collect the data. Permission was obtained from the USAID to gain access to the anonymized and aggregated freely available dataset from the DHS online data archive .n = 48) households, while biomass fuels and kerosene were used in 99.6%  of the households. Overall 11% (n = 2168) of the household respondents reported cooking to be performed inside the main residential house, of which 68% (n = 1478) did not have a separate room as a kitchen. The dominant household cooking fuel was mostly charcoal in urban areas  and wood in rural areas  , with 986 births (9.6%) classified as LBW . Of thes, 83.7%) . Cleaner, 83.7%) . In the bivariate analysis, a borderline association was observed between LBW in households using wood cooking compared to other biomass fuels  . Howeverp = 0.393). In the sensitivity analyses, which included the addition of all available confounders including mothers BMI, the timing of ANC visit, and number of ANC visits, no significant association  was found among households where wood compared to other biomass fuels were used.Place of residence, cooking location, and adjustment for maternal BMI in sensitivity analyses all had no observed association of LBW between births from wood cooking compared to other biomass cooking households . BirthweThis population-based study of 15,270 live-births and a high response rate (97%) in Uganda was conducted to determine the association between wood compared to kerosene and other biomass cooking fuels with the risk of LBW. No evidence of an association was observed between the different types of biomass and kerosene fuels and risk of LBW  after adjustment for confounding factors. In the sensitivity analyses which considered the associated effect of residence , cooking location , maternal BMI, and birthweight as a continuous dependent variable with risk of LBW, findings similar to the main analyses were found.LBW was observed to occur among almost 10% of all deliveries which, although lower than the 14% previous estimates for Sub-Saharan Africa , which tTo the best of our knowledge, this was the first study in Uganda to determine the association between the different types of biomass fuels and LBW, a setting where biomass fuels were used by almost all (99.6%) of the population; limiting the possibility of comparing biomass fuels to cleaner fuels. The DHS collects robust, nationally representative data, however, there were a large (32.8%) number of missing birthweights recorded. However, 67.2% of birthweights were recorded totaling 15,270 live-births. Birthweights obtained by maternal recall may have been subject to recall bias, but this was reduced by limiting the data collection period to births within the last five years. Although there was no evidence of an effect in our study and the reference cooking fuel differs to that of other studies, they are similar to those obtained in single-country analyses investigating the difference between biomass and cleaner fuels in Malawi  ), Ethiop2.5, CO, and aromatic hydrocarbons [There is evidence for the biological plausibility of LBW risk associated with in-utero HAP exposure including PMocarbons ,49. Incrocarbons ,12,50. Eocarbons ,49. Reduocarbons ,49,51. TCharcoal was predominantly used in urban settings, and wood was mostly used in rural settings, but no difference in odds of LBW risk was observed between rural and urban areas. In settings where biomass fuels are mostly used and access to cleaner fuels remains limited, feasible mitigation measures should be promoted to reduce exposure to HAP among vulnerable women and children under five years of age . The mit2.5 and CO which exceed WHO-AQGs [Although improved cookstoves can still emit levels of PMWHO-AQGs , a reducWHO-AQGs . GovernmWHO-AQGs .Proxy measures may be reliable and valid ways of estimating HAP exposure, however, the inability to use direct measures of HAP may have resulted in misclassification bias and inaccurate estimation of HAP. Further DHS data collection should endeavor to check birthweight against health card and capture use of secondary cooking fuels, stove type, alongside fuel and stove stacking practices . Future In this study, almost all (99.6%) study households in Uganda used biomass and kerosene fuels for domestic cooking, with LBW observed among 9.6% of singleton live births. After adjusting for household, maternal and demographic confounding factors, no evidence of an association was observed between risk of LBW and the use of wood fuel compared to other biomass or kerosene cooking fuels. Although previous evidence has indicated reduced risks of LBW with cleaner fuels, this requires further investigation, as the very low proportion of LPG, electricity or biogas use meant a comparison of risks associated with biomass fuels could not be undertaken in this present study. Achieving energy policy targets for adoption of cleaner fuels by 2040 in Uganda remains a key policy priority given the existing high reliance upon polluting biomass fuels. Public health initiatives to reduce LBW prevalence should seek to reduce socio-economic inequity and increase levels of female education in this context.


Additionally, we found that Tibetans from Ü-Tsang/Ando/Kham regions showed a strong population stratification consistent with their cultural background and geographic terrain. Ü-Tsang Tibetans possessed a stronger Chokhopani-affinity, Ando Tibetans had more Western Eurasian related ancestry and Kham Tibetans harbored greater Neolithic southern EA ancestry. Generally, ancient and modern genomes documented multiple waves of human migrations in the TP’s past. The first layer of local hunter-gatherers mixed with incoming millet farmers and arose the Chokhopani-associated Proto-Tibetan-Burman highlanders, which further respectively mixed with additional genetic contributors from the western Eurasian Steppe, Yellow River and Yangtze River and finally gave rise to the modern Ando, Ü-Tsang and Kham Tibetans.Archeologically attested human occupation on the Tibetan Plateau (TP) can be traced back to 160 thousand years ago (kya) via the archaic Xiahe people and 30∼40 kya via the Nwya Devu anatomically modern human. However, the history of the Tibetan populations and their migration inferred from the ancient and modern DNA remains unclear. Here, we performed the first ancient and modern genomic meta-analysis among 3,017 Paleolithic to present-day Eastern Eurasian genomes . We identified a close genetic connection between the ancient-modern highland Tibetans and lowland island/coastal Neolithic Northern East Asians (NEA). This observed genetic affinity reflected the primary ancestry of high-altitude Tibeto-Burman speakers originated from the Neolithic farming populations in the Yellow River Basin. The identified pattern was consistent with the proposed common north-China origin hypothesis of the Sino-Tibetan languages and dispersal patterns of the northern millet farmers. We also observed the genetic differentiation between the highlanders and lowland NEAs. The former harbored more deeply diverged Hoabinhian/Onge-related ancestry and the latter possessed more Neolithic southern East Asian (SEA) or Siberian-related ancestry. Our reconstructed  Homo sapiens. The present-day Tibetans are suggested to have uniquely adapted to the extreme high-altitude conditions since the initial colonization of the TP (HIF-1α prolyl hydroxylase1 (EGLN1) and Endothelial PAS domain protein 1 (EPAS1) were introduced into modern Tibetans and surrounding highlanders via the Denisovan introgression, which further promoted Tibetan’s high-altitude hypoxia adaptation (The Tibetan Plateau (TP), widely known as the third pole of the world, forms the high-altitude core region of Asia with an average elevation more than 4,000 meters above sea level (masl). The TP represents one of the most challenging environments for human settlements due to the perennial low temperature, extreme aridity, and severe hypoxia. However, archeological and genetic studies have demonstrated that archaic hominins who occupied the TP had well adapted to the high-altitude hypoxic environment long before the arrival of modern f the TP . Howeverf the TP . At presf the TP . For exaaptation . Compareaptation , the popHomo sapiens found at the Quesang site in southern TP  suggested that the intermittent human presence on the TP could trace back to at least 20 kya . Besides, the lack of discussion of ancient samples from the TP and incomprehensive analysis of ancient/modern individuals from East Asia hindered our ability to spatiotemporally connect dispersed ancient East Asians and modern Tibetans. Thus, we comprehensively meta-analyzed the genetic variations of ancient/modern highlanders from the TP and surrounding lowland eastern Eurasians with the aims to (I) portray the genetic landscape of the East Asian highlanders, (II) study the genetic similarities and differences between highlanders and lowlanders, (III) explore the genetic substructure among geographically/culturally different Tibetans, (IV) reconstruct their deep evolutionary history and the corresponding migration and admixture processes. By analyzing genome-wide data of modern Tibetans and Neolithic-to-historic individuals from East Asia, we shed light on the genetic transition, turnover or continuity, ancestral composition, and demographic history of Tibetan highlanders.We collected 2,444 individuals from 183 geographically/culturally different populations  belonginsmartpca program of the EIGENSOFT package  with the  package  using th package   when we used 10 predefined ancestral sources.We carried out the model-based clustering analysis using the ADMIXTURE (v.1.3.0)  after prqp3Pop program implemented in the ADMIXTOOLS f to assess the shared genetic drift between our focused Tibetans and their reference populations. A central African population Mbuti was used as the outgroup. Admixture-3f were performed to test whether our targeted population was an admixture of two sources related to our used surrogate populations. Negative f3-values with a Z-score smaller than −3 indicated that two source populations were admixed to form the targeted populations. Four-population comparisons were conducted using qpDstat programs implemented in the ADMIXTOOLS (f4: YES) in three different forms. The first one was conducted in the form of 4f to test whether two Tibetans form one clade relative to the used Eurasian reference. Non-statistically significant f4 values showed two left populations formed one clade. Other two f4-statistics in the forms 4f and 4f were conducted to examine whether the used ancestral source shared more alleles with one of the Eurasians compared with others. We assessed standard errors using the weighted block jackknife approach. We next used the qpGraph program implemented in the ADMIXTOOLS  onto the genetic background of modern populations. Here, we found four ancient population genetic clusters. Neolithic-to-historic SEAs  grouped together and clustered with modern Tai-Kadai, Austronesian, and Austroasiatic speakers. Neolithic-to-Iron Age NEAs  grouped together and were projected closely to the juncture position of three main East Asian genetic lines and the northmost end of Han Chinese genetic cline. We observed a close genetic relationship between early Neolithic Houli individuals associated with the main subsistence strategy of hunter-gathering and the Henan Middle/Late-Neolithic Yangshao/Longshan farmers, which indicated the genetic continuity in the Neolithic transition from foragers to millet farmers in the early Neolithic northern China. We also identified the subtle genetic differences within these Neolithic-to-Iron Age individuals from northern China. These Shandong Houli individuals were localized closely with modern Mongolic-speaking Baoan, Tu, Yugur, and Dongxiang, while the early Neolithic Xiaogao individuals were posited closely with modern Tungusic-speaking Hezhen and Xibo. All Shandong Neolithic ancient populations were localized distantly from the modern Shandong Han Chinese and shifted to modern northern Chinese minorities, which indicated that modern northern Han received additional gene flow from SEA related ancestral lineage or ancient Houli individuals harbored more Siberian-associated ancestry. Late-Neolithic Longshan individuals  and Bronze/Iron Age individuals  in Henan province were grouped together and shifted to the Han Chinese genetic cline and partially overlapped with Han Chinese from Shanxi and Shandong provinces. This observed genetic similarities among the Late Neolithic to present-day NEAs from the Central Plain  indicated a genetic stability in the core region of Chinese civilization since the Late-Neolithic period. Middle-Neolithic Yangshao individuals (Xiaowu and Wanggou) in Henan province grouped with some of the Wuzhuangguoliang_LN individuals collected from Shaanxi province and were shifted to more northern modern minorities. The inland Middle/Late-Neolithic NEAs from Shaanxi (Shimao), Inner Mongolia (Miaozigou) and upper Yellow River (Lajia and Jinchankou) clustered together and were shifted toward modern Tibetans and ancient Nepal samples .For ancient populations from the West Liao River, three genetic-affinity clusters could be identified in the projected PCA results: northern cluster (Haminmangha_MN and Longtoushan_BA_O) showed a genetic affinity with Shamanka and Mongolia Neolithic people; middle Hongshan cluster was localized between Mongolia minorities and modern Gangcha Tibetan; southern cluster (Upper Xiajiadian Longtoushan_BA and Erdaojingzi_LN) possessed close relationship with the Yellow River farmers, which suggested that both Neolithic ancients associated with steppe pastoralists from Mongolia Plateau and millet farmers from Yellow River Basin had participated in the formation of the Late Neolithic and subsequent populations in the West Liao River Basin. These population movements, interactions, and admixture processes have recently been fully elucidated by Patterns of genetic relationship revealed from the top two components (extracting 1.42% variation: PC1: 1.03% and PC2: 0.39%) showed a genomic affinity between modern Tibetans, ancient Nepal populations, and ancient/modern East Asians and Siberians. To further explore the genetic structure and corresponding population relationships, we estimated the ancestry composition and cluster patterns according to the model-based maximizing likelihood clustering algorithm . We obseFST genetic distances among 82 modern populations  and the Kham Tibetans from the southeastern region of the TP (Sichuan and Yunnan) and other Tibeto-Burman-speaking populations . For Ando Tibetans from the Ganqing region, Gangcha Tibetan harbored a close genetic affinity with northern or northeastern Tibet Tibetans (Chamdo and Nagqu) with the smallest FST genetic distances, followed by Qiang, Yugur, and Tu or other geographically close Tibetans f. We found a close genetic affinity within Tibetan populations and identified the genetic connection between Tibetan and Han Chinese. Among 184 modern populations  inferred from the outgroup-imations . Middle-imations . Neolithimations . Differef3-statistics in the form 3f to detect the signals of recent genetic admixture in Tibetans. We also re-evaluated the admixture signatures in the eight ancient individuals from Nepal and eleven ancient individuals from Qinghai province using this three-population comparison testing and our comprehensive ancient/modern reference dataset. We found different patterns of admixture signals and source populations in the highland/lowland ancient/modern Tibetans  in 3f. Tibetans from southern and central Tibet combined with the lowland modern East Asians, but not with ancient East Asians, could also produce significant admixture signals for Nagqu Tibetan f = −∗SE3.49 f showed that the combination of inland Neolithic NEA of Yumin_EN as northern ancestral source with Austronesian/Tai-Kadai speakers as the southern ancestral source could produce significant negative f3-values, and these admixture signals could also be identified in 3f. Tibetans from Sichuan province only showed significant signals as an admixture between northern and southern East Asians or the highland Tibeto-Burman speakers and lowland East Asians, i.e., 3f < −∗SE3 f, in which we expected to observe the non-significant f4-values if no significant differences existed between different Tibetan groups. As shown in 4f and all included Tibetans shared more alleles with Chamdo Tibetan compared with Ando Tibetans. Compared to the low-altitude Sichuan Tibetans, Chamdo Tibetan had more high-altitude Tibetan-related ancestry, while Gannan Tibetan shared more alleles with Xinlong Tibetan compared with Chamdo Tibetan. Compared with high-altitude Tibetans, Chamdo Tibetan shared more alleles with other low-altitude Tibetans. Results from the symmetry-4f with non-significant Z-scores showed clear genetic homogeneity among Tibet central/southern-Ü-Tsang Tibetans f showed that all included Tibetans shared more alleles with southern Tibet Tibetans relative to Gansu-Qinghai Ando Tibetans. However, northern Tibet Tibetans formed a clade with Chamdo and Yunnan Tibetans and received more high-altitude Tibetan-related derived alleles compared with Gansu-Qinghai and Sichuan Tibetans. For lowland Tibetans, northwestern Tibetans in Gangcha and Xunhua formed one clade, i.e., all absolute Z-scores of 4f were less than three f were larger than zero. Southwestern Yunnan Tibetan formed one clade with Chamdo/Xinlong/Yajiang Tibetans, all of them belonged to Kham Tibetans f. The non-significant Z-scores in 4f confirmed the genomic homogeneity within the four high-altitude Ü-Tsang Tibetans. We could also identify the more allele sharing between the Nepal ancients and Ü-Tsang Tibetans compared to Ando and Kham Tibetans f, which suggested that Ando Tibetans harbored increased ancestry related to steppe pastoralists, such as Sintashta, Yamnaya, Afanasievo, Srubnaya, Andronovo and Xinjiang Iron Age Shirenzigou populations. Although strong genetic affinity within Ando Tibetans was confirmed with the similar patterns of f4-based sharing alleles and non-significant statistical results in symmetry-f4 statistics. Statistically significant negative f4-values in 4f showed that Gannan Tibetan harbored increased SEA ancestry related to modern Austronesian or Proto-Austronesian-related Neolithic to present-day southeastern coastal/island populations f revealed the similar genetic relationship between modern Tibetans and these different Neolithic NEAs f only revealed Luoheguxiang people had increased ancestry associated with modern Austronesian-speaking Ami f was used to determine the lowland and highland East Asian affinity. Compared with four coastal Neolithic Shandong populations, we found that Ü-Tsang Tibetans had a strong highland East Asian affinity. Besides, comparison against the coastal and inland ancients revealed that modern Tibetans had a strong inland-NEA-affinity, especially with Late Neolithic Lajia people from the upper Yellow River. This Lajia-affinity or inland-NEA-affinity persisted when we substituted inland Yumin_MN with the coastal Neolithic NEAs f. We further tested if one single source could explain the observed genetic variations in Tibetans. We first assumed that modern Tibetans were the direct descendants of SEAs which is associated with the Yangtze Rice farmers. As shown in f4-values in 4f when we used NEAs/Siberians as the reference populations, which indicated obvious gene flow events from these reference populations into modern Tibetans. We then assumed that Tibetans’ direct ancestor was coastal Neolithic-NEAs, we conducted 4f and found only Nepal ancients showed the negative-f4-values, which was consistent with the common origin of the Sino-Tibetan speakers from YRB  showed that at least two ancestral populations were needed to explain the observed genetic variations in targeted populations. We first employed the two-way model of Onge and six inland/coastal early Neolithic-NEAs and found inland Yumin failed to fit our targeted populations’ genetic variations . The two-way model “Xiaogao_EN-Onge” could fitted all modern Tibetans well except for Gannan Tibetan with the Xiaogao-related ancestry proportion ranging from 0.846 in Shannan Tibetan to 0.906 in Xinlong Tibetan. The 2700-year-old Chokhopani, like geographically close Shigatse Ü-Tsang Tibetans, could be fitted as an admixture of 0.861 NEA Xiaogao-related ancestry and 0.139 Onge-related ancestry  as the western Eurasian source in a three-way admixture model to fit the genetic variations in Ando Gangcha and Gannan Tibetans and Samdzong. All three populations could be successfully fitted when we introduced the Bronze Age steppe pastoralists’ related ancestry.From the autosomal perspective, we found the close connections of modern Tibetans and Neolithic NEAs. From a paternal Y chromosomal perspective, Tibetan shared a genetic affinity with Andamanese Onge and Jomon hunter-gatherers from the Japanese archipelago . Onge anancestry . YoungerqpGraph. The core model of our admixture graph included archaic Denisovan and central African Mbuti as the roots, Loschbour as the representative of western Eurasian, modern Onge hunter-gatherer from Andaman island and 40,000-year-old Tianyuan (3% ancestry from Denisovan) as representatives of deep lineages of southern East Eurasian and northern East Eurasian. As shown in Finally, to comprehensively summarize the phylogenetic relationships and reconstruct the population history between Neolithic East Asians and modern Tibetans in one phylogenetic framework, we built a series of admixture graph models via qpGraph-based phylogenetic frameworks  and did not identify significant f4-values, which suggested that highland and lowland East Asians formed a clade relative to the Denisovan and both harbored equal levels of Denisovan related ancestry. Similar patterns of archaic admixture between Neolithic East Asians and modern East Asians were also evidenced in a recent study on ancient DNA  was derived from the common NEA lineage related to East Mongolia Neolithic people and Yangshao/Longshan/Houli people from the Central Plain in northern China. Thus, our results in this meta-genomic analysis supported the main lineage that contributed to TP people originated from the Upper and Middle Yellow River with the Neolithic expansion of millet farmers. Our analysis confirmed the origin, diversification, and expansion of the modern Sino-Tibetan populations revealed by the mitochondrial and Y-chromosome variations . Thus, our meta-analysis provided new robust evidence for the co-existence of both Paleolithic and Neolithic ancestries in the gene pool of East Asian highlanders as well as the Paleolithic colonization and Neolithic expansion of TP people, which was previously clarified via the modern whole genomes, mitochondrial and Y-chromosomal data  proportion of Paleolithic hunter-gatherer ancestry related to the early diverged deep eastern Eurasian lineages (Onge or Hoabinhian related lineages). mal data .qpGraph-based model; Kham Tibetans from Sichuan and Yunnan provinces possessed a strong southern Neolithic East Asian affinity. Thus, population substructures observed in modern Tibetans were consistent with the geographic and cultural divisions, which suggested that the complex cultural background and terrain to some extent served as the barriers for population movement and admixture. Our qpGraph-based phylogeny revealed the gene flow from southern Iron-Age East Asians into Kham Tibetans, from Neolithic NEAs into Kham and Ü-Tsang Tibetans, from western Eurasians into Ando Tibetans, which demonstrated multiple waves of migrant influx from the Siberia, northern and southern East Asia had shaped the gene pool of Tibetan highlanders.Additionally, we also found obvious population substructures among modern Tibetans: Ü-Tsang Tibetans in Tibet core region had predominant original Paleolithic and Neolithic ancestries; Ando Tibetans from Gansu-Qinghai region in northwest China had 2∼3% western Eurasian related ancestry via We performed a comprehensive genomic meta-analysis focused on Neolithic to present-day people to clarify the relationship between the TP highlanders and lowland East Asians and to explore the peopling of TP. We found a strong genetic affinity between Tibetans and Neolithic to present-day NEAs, which suggested Tibeto-Burman speakers originated from the Upper and Middle YRB in northern China. The observation of the shared ancestry between Han Chinese and Tibetans was consistent with the co-dispersal of millet farmers and Sino-Tibetan languages. Although the shared ancestry persisted between ancient Tibetans and lowland Neolithic people (Yangshao/Longshan/Houli culture), we also found genetic differentiation between them: highland Tibetans harbored more deeply diverged eastern Eurasian Onge-related hunter-gatherer ancestry, but the lowland Neolithic to present-day NEAs possessed more ancestry related to the Neolithic SEAs and Siberians, which not only suggested the co-existence of Paleolithic and Neolithic ancestries in ancient/modern Tibetans but also illuminated the population history of Paleolithic colonization and Neolithic expansion. Besides, consistent with the geographic/linguistic divisions, we identified population substructures in modern Tibetans: more Onge/Hoabinhian related ancestry in Ü-Tsang Tibetans, much more western Eurasian related ancestry in Ando Tibetans, and more Neolithic SEA related ancestry in Kham Tibetan. In short, modern East Asian highlanders derived their ancestry from at least five waves of population admixture: Hoabinhian as the oldest Paleolithic layer; additional gene flow from two Neolithic expansions  from NEAs, one Neolithic SEA northwestward expansion and one western Eurasian eastward expansion.qpGraph-based phylogenetic frameworks.The Tibetan Plateau has a harsh and extreme high-altitude hypoxic environment, which is inhospitable for human permanent settlement. The population genomic history of modern Tibetans and the population dynamic demographic history of their predecessors need to be comprehensively characterized. We used one large-scale modern and ancient Eurasian meta-dataset to perform genomic analyses focusing on the fine-scale population structure of modern and ancient East Asian highlanders. Firstly, we identified the genomic affinity between highlanders and Neolithic-to-modern Northern East Asians, which was in accordance with the archeologically documented phenomena of Neolithic millet farmer expansion from the Yellow River Basin with the dissemination of Tibeto-Burman languages. Secondly, we identified the obvious population substructure in modern Tibetans along with their cultural division. Thirdly, we documented multiple waves of peopling the Tibetan Plateau and the complex admixture history of East Asian highlanders via the The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/ The studies involving human participants were reviewed and approved by this project was inspected and approved by the Medical Ethics Committee of the Xiamen University. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.GH, RT, C-CW, H-YY, and MW conceived the idea for the study. GH, MW, XZ, PC, ZW, YL, HY, and L-HW performed or supervised wet laboratory work and analyzed the data. GH, MW, and XZ wrote and edited the manuscript. All authors contributed to the article and approved the submitted version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer JH declared a past co-authorship with the authors GH, XZ, C-CW, L-HW, H-YY to the handling editor.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


M age = 8.45, SD = 1.40, 17.4% girls) with the diagnosis of ADHD were recruited in this study. Participants wore a wGT3X-BT accelerometer on their wrist for seven consecutive days to measure PA. Motor competence was measured by the Test of Gross Motor Development-Third Edition (TGMD-3). Quality of life (QoL) was assessed by the parent-reported Chinese version of the Pediatric Quality of Life Inventory. MVPA was positively associated with object control skills but was not directly related to QoL. Using the bootstrapping method, the indirect effect of object control was found between MVPA and social functioning , school functioning , and overall QoL , supporting the full mediation effect. Moderated mediation analysis further revealed that age strengthened the indirect effect from MVPA to social and school functioning via object control. Findings of this study indicated that MVPA is positively associated with object control skills, which in turn, is related to psychological aspects of QoL in children with ADHD. Age was found to moderate the indirect mediation paths. The findings may inform future expeditions on designing an effective intervention that helps to improve MC and QoL in children with ADHD.This study examined the mediating role of motor competence in the association between physical activity (PA) and quality of life (QoL) and the moderating role of age in the indirect relationship between PA and QoL in children with ADHD. Eighty-six children aged 6-12 years old ( Attention deficit hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder characterized by age-inappropriate inattention, impulsivity, and hyperactivity  that affThere is a growing realization that psychiatric comorbidity is the “rule rather than the exception”  ; school functioning: b = 0.03, SE = 0.02, 95%CIboot = ). However, the indirect effect was not significant for younger children with ADHD . Results showed that object control mediated the effect of MVPA on QoL, but a younger age weakened the mediating effect of object control.The bias-corrected percentile bootstrap analysis further indicated that the indirect effect of MVPA on social and school functioning via object control was moderated by age. Specifically, the indirect effects of MVPA on social and school functioning were significant for older children with ADHD  and general level of QoL. Previous studies found that exercise interventions with high levels of PA might improve both motor skills and physical health of QoL in children with ADHD . HoweverLastly, our findings indicate that age could moderate the relation between MVPA and object control skills as well as indirect path between MVPA and QoL. The relationship between MVPA and MC turns to be stronger in older children in comparison to younger children with ADHD. Plausible explanation could be that as ADHD children getting older, physical activity participation is more facilitative for shaping motor skills. These findings, to some extent, confirm the previous speculations that the relationship between PA and MC evolves as children age . AdditioThe current study had several strengths . However, several limitations should be addressed. First, although it was recommended that the appropriate sample size to test a medicating effect using the bootstrapping method should be at least ranging from 50 to 100 participants , the relAlthough further replication and extensions are necessary, the present study is an important step in unpacking how MVPA relates to various aspects of QoL of children with ADHD. Since MC served as one potential mechanism by which MVPA were correlated to QoL, it remains important to address motor impairment directly or intervene in a manner that promote the impact of MVPA on QoL. Our results may inform future expeditions of how nonpharmacological intervention  may help to improve MC, and therefore, QoL in children with ADHD. Particularly, age-appropriate strategies with increased MC-oriented intervention could help children with ADHD maximize benefits on health-related outcomes.


Both functional abdominal pain disorders (FAPDs) and food allergies are relatively common in children and adolescents, and most studies report an association between FAPDs and allergic conditions. FAPDs share pathophysiologic processes with allergies, including both immune and psychological processes interacting with the microbiome. No conclusive data are implicating IgE-mediated reactions to foods in FAPDs; however, there may be patients who have IgE reactions localized to the gastrointestinal mucosa without systemic symptoms that are not identified by common tests. In FAPDs, the data appears stronger for aeroallergens than for foods. It also remains possible that food antigens initiate an IgG reaction that promotes mast cell activation. If a food allergen is identified, the management involves eliminating the specific food from the diet. In the absence of systemic allergic symptoms or oral allergy syndrome, it appears unlikely that allergic triggers for FAPDs can be reliably identified by standard testing. Medications used to blunt allergic reactions or symptomatically treat allergic reactions may be useful in FAPDs. The purpose of the current manuscript is to review the current literature regarding the role of allergy in FAPDs from a clinical perspective, including how allergy may fit in the current model of FAPDs. Chronic or recurrent abdominal pain is common in children and adolescents, with a worldwide prevalence estimated at 13.5% . The recThere has been increasing interest in the role of diet in FAPDs. Perceived food intolerances are common in pediatric FAPD patients, with over 90% identifying at least one food they associate with worsening symptoms . These pThe separation between food allergy and intolerance has become increasingly blurred as some food intolerances can start a chain of events resulting in mucosal immune activation. For example, lactose malabsorption is a well-recognized food intolerance. In most studies, lactose restriction does not result in clinical improvement even in patients with demonstrated malabsorption ,10,11,12Food allergy refers to developing symptoms resulting from an immune reaction  to an ingested antigen. Food allergies are divided into two categories: IgE- mediated and non-IgE-mediated. IgE-mediated reactions are associated with more rapid onset of symptoms, while non-IgE-mediated reactions typically result in delayed onset of symptoms ,27. FoodBoth FAPDs and food allergies are relatively common in children and adolescents and may be linked in at least a subset of patients. The purpose of the current manuscript is to review the current literature regarding the role of allergy in FAPDs from a clinical perspective, including how allergy may fit in the current model of FAPDs. Although the focus is on pediatric FAPDs, we will also incorporate the more abundant adult literature relevant to adolescents.The complex nature of chronic abdominal pain has long been viewed within the context of the biopsychosocial model, which recognizes that various interacting factors contribute to the initiation and maintenance of pain. These contributors include biologic factors , psychologic factors , and social factors . There appear to be four main host systems involved in symptom generation which interact readily with each other, including psychologic, neurologic, immunologic, and endocrinologic systems, all of which interact with the gastrointestinal microbiome. A central mechanism appears to be visceral hypersensitivity, an exaggerated response to stimuli such as gastrointestinal distension. Hypersensitivity to distension has been demonstrated in youth with chronic abdominal pain ,31,32.Given that allergy involves an immunologic reaction, the role of inflammation, particularly mast cell-related, within the biopsychosocial model appears to be most relevant to the current discussion See . Mast ceThere is considerable evidence implicating inflammation in FAPDs, particularly mast cells  in IBS and both mast cells and eosinophils in FD ,36,37,38Psychologic function is an important component of the biopsychosocial model and may directly relevant to a discussion of allergy. FAPDs are associated with psychologic dysfunction, including anxiety, depression, and maladaptive coping . PsycholMost, but not all, studies have shown an association between FAPDs and allergic conditions . FD and Interestingly, a placebo-controlled trial of a probiotic (Bifidobacteria) in children with allergic rhinitis in association with intermittent asthma demonstrated significant improvement in allergic rhinitis symptoms . These fNo conclusive data is implicating IgE-mediated reactions to foods in FAPDs ,71. The There may be patients who have IgE reactions localized to the gastrointestinal mucosa without systemic symptoms who are not identified by SPT or serum food-specific IgE. Methods are available to evaluate localized reactions in the gastrointestinal tract, including the colonoscopic allergen provocation test  and visualization utilizing confocal laser endomicroscopy (CLE). Utilizing COLAP, positive reactions to food antigens are recognized by the wheal and flare reactions occurring within 20 min of antigen application. Reactions are associated with mast cell degranulation eosinophil activation histologically . In a stStaphylococcus aureus and Streptococcus pyogenes, are more commonly present in the microbiome of IBS patients [Staphylococcus aureus in patients with atopic dermatitis has been associated with an increased risk of food allergy [Recent studies in a mouse model demonstrate potentially important interactions with bacterial infection or colonization in predisposing to these localized intestinal allergic reactions . In thispatients . Skin co allergy . Likewis allergy .In FAPDs, the data appears stronger for aeroallergens than for foods . As discFood antigens may precipitate gastrointestinal symptoms through cell-mediated processes  elevations, will result in unnecessary diet restrictions without long-term benefit and could lead to nutritional deficiencies. In patients with only gastrointestinal symptoms, allergy testing is not likely to be helpful, either in identifying the culprit or in providing a list of safe foods. Patients who develop systemic allergic symptoms or those with oral allergy syndrome should be referred to an allergist for directed testing and management of identified allergens. This should not be a transfer of care but the formation of a collaboration to manage the patient. Another approach is an empiric restriction of the most common allergens used in the treatment of eosinophilic esophagitis. Unfortunately, there is very little data assessing this approach in patients with eosinophilic gastroenteritis, let alone FAPDs, and no randomized trials ,113. InsWhile the patient would be expected to benefit from removing food allergens or managing aeroallergens if identified, it remains unlikely that gastrointestinal symptoms will completely resolve without addressing other biopsychosocial aspects of these disorders as allergens are only one trigger for activating gastrointestinal mast cells. See For patients with primarily gastrointestinal symptoms who do not have systemic symptoms typical of allergic reactions or oral allergy syndrome, it is unlikely that specific triggering allergens will be identified even if they exist as current tests likely lack adequate sensitivity or specificity. The challenge is that end-organ inflammatory processes do not necessarily identify patients who specifically have allergic triggers, as mast cells and eosinophils appear to be a common component of FAPDs. Another approach would be to direct treatment at the mast cells and/or eosinophils without regard to whether their activation is due to an allergen. As with non-gastrointestinal allergic diseases, treatment can be directed at mast cell activators , mast cell mediator release , or inhibition of mast cell mediators  at their effector sites . Most haThere are no FDA-approved drugs for the treatment of gastrointestinal eosinophils . MultiplThe largest body of data, albeit somewhat meager, exists for mast cell stabilizing medications, including oral cromolyn and ketotifen. Two placebo-controlled trials have assessed the response to ketotifen, a mast cell stabilizer and H1 antagonist, in adults with IBS, with both demonstrating improvement in abdominal pain and other IBS symptoms ,121. VisMedications used in other allergic conditions to inhibit the actions of mediators released from mast cells and eosinophils may also be beneficial in FAPDs, although the current evidence is limited. See  Most stuFAPDs share pathophysiologic processes with allergies, including both immune and psychological processes interacting with the microbiome. Although there is significant overlap in the medications that can be used for allergic disorders and FAPDs , it is unclear to what degree allergens play a role FAPDs. In the absence of systemic allergic symptoms or oral allergy syndrome, it appears unlikely that allergic triggers for FAPDs can be reliably identified by standard testing. There is a need for high-quality studies assessing dietary strategies and anti-allergy medication to better understand the efficacy and the value of allergy tests to predict response.


The current study investigated longitudinal associations between parent-rated temperament, observed exuberance and accelerometer activity level at 18-months and symptoms of ASD and ADHD at 36-months in a sample of 54 children at elevated likelihood for ASD. For the specific parent-rated temperament scales, most observed significant associations appeared to be specific for either ASD or ADHD symptoms. Indeed, by controlling for overlapping symptoms a different pattern of associations emerged. These results illustrate how temperamental measures may signal risk for later ASD versus ADHD symptomatology in infants at elevated likelihood for ASD. In addition, they indicate the potential of adopting a broader view on neurodevelopmental disorders by investigating not only ASD traits, but also co-occurring disorders such as ADHD in samples of elevated likelihood for ASD. Autism Spectrum Disorder (ASD) is defined by social communication deficits and repetitive and restricted behaviors . Individuals with ASD often have co-occurring conditions, such as attention-deficit/hyperactivity disorder (ADHD), which is characterized by a persistent pattern of inattention and/or hyperactivity/impulsivity  can be identified during the first year of life whereas the third regulatory factor (effortful control), develops during the second year of life when the child becomes more consciously aware , following infants from 5 months until 6 years of age. Here, we use data from assessments at 18- and 36-months of age. The reason for selecting the 18-months assessment was that we wanted to use the bubble task in the ADOS-2 as an early indicator of exuberance/activity, and 18 months is the earliest time point we have this measure on all participants. The 36-month (rather than the 6 year) time point was selected to increase sample size for the analysis (most children have not yet reached 6 years). Informed consent was given by the parents prior to conducting the assessments.At time of enrollment, the infants had at least one older sibling diagnosed with ASD, based on the presence of a community clinical diagnosis. The majority of the community clinical assessments for the diagnosed sibling included both the ADOS-2 and ADI-R, considered gold standard measures for diagnosing ASD. Exclusion criteria at the point of recruitment included birth before 36 weeks of gestation, visual or auditory impairment, or any known medical or genetic conditions. Families in the study were recruited from clinical units, advertisements and the project’s web page. Socioeconomic status was calculated as the mean of level of family income rated on a scale from 0 to 5 and parent educational level rated on a scale from 1 to 5, expressed as Z scores and is reported in Table t = 0.40, p = 0.68) and Pervasive Developmental Problems . Out of the 74 children of the 77 children who had diagnostic data at 3 years, 27 (36%) children had received an ASD diagnosis at 3 years. The control group, consisting of children with typical likelihood, was too small (N = 22) to make proper comparisons, and hence not included in the analysis. In addition, our research questions motivated examining the group of children at elevated likelihood for ASD specifically. Descriptive and inferential statistics on background data is summarized in Table The initial sample consisted of 86 children at elevated likelihood for developing an ASD diagnosis. Out of these, 9 children were excluded from the analysis because of technical problems during video-recording resulting in a sample of 77 children. A drop-out analysis showed that there was no difference between the excluded and the included children who had data on the 18 months CBCL scales for ADHD . The study was conducted in accordance with the 1964 Declaration of Helsinki.Temperamental exuberance was assessed from the bubbles task in the ADOS-2 Toddler . We chose this task due to the similarities with the bubble task used to measure exuberance in the Laboratory Temperament Assessment Battery , a standardized task with a valid coding schedule. We used the coding schedule from the Lab-Tab as a template for developing a customized coding schedule that was better suited for the bubble task in ADOS-2 which we used in the current study. In this task an examiner blows bubbles and plays with the child for a brief period of time. The task also involves a part where the examiner “teases” the child by first offering the bubble machine to the child and then removing the bubble-toy when/if the child reaches for the toy. A customized coding schedule was developed in order to catch relevant behaviors from the bubble task in ADOS-2 . Activity level, positive affect and sociability were coded in 15-s intervals on a 1–5 scale, with 1 being the lowest score and 5 being the highest score. To use activity level as an example, we used the following criteria; (1) represents no motor activity , (2) describes limited motor activity , (3) was used for moderate motor activity , (4) was used for active motor activity , and (5) was used for intense motor activity . See Supplementary Material for full descriptions of the scales. The segment codes were then used to decide on a global score for each variable, which in turn were used as dependent measures. The rationale for this approach was that some children may take time to warm up, wherefore an estimate global score seemed more appropriate to use than computing averages based on the segments. The global score was a total score based on the total 2.5-min task for each variable coded on the same 1–5 scale as for the segment scores. We used the global score as a dependent measure for this task.N = 30) of the data. Intraclass correlation (ICC) estimates were calculated based on the mean-rating (k = 3) absolute agreement, 2-way mixed effect model. The average ICC coefficients were 0.76 for activity level, 0.88 for positive affect, and 0.70 for sociability. All ICCs were considered as indications of good interrater reliability  and a mean estimate was used as a score of exuberance.The scales Bodily fear, Facial sadness and Distress were omitted from further analyses due to no variations in this particular task. The scales Proximity to parent, Latency to approach and Degree of approach was omitted from further analyses to limit the amount of analyses. Three coders, unaware of ASD likelihood status, were initially trained to reach acceptable levels of agreement. Double-coding was done on 43% , α = 0.65 for Frustration, α = 0.72 for Motor activation, α = 0.81 for Perceptual sensitivity, α = 0.88 for Shyness, and α = 0.88 for Soothability. Finally, Cronbach’s alpha for the behaviors included in the Effortful control factor were; α = 0.92 for Inhibitory control, α = 0.86 for Attention focusing, α = 0.75 for Attention shifting, α = 0.86 for Low-intensity pleasure, and α = 0.90 for Cuddliness. Alpha levels for all scales fell within the reasonable to excellent reliability range , we used small portable accelerometers  which recorded the 3D acceleration of the arm. The Q-sensors are worn on the wrist of the child, and records arm movements by accelerometers along the x, y and z axis of the device in gravity units (i.e. a completely still sensor records 1 G). Movement activity level was calculated by transforming these axes to a three-dimensional space and computing the root mean square (RMS) of all samples in the 3D acceleration profile. Because some of the infants took a nap during the visit, the acceleration time series were segmented into bins with a duration of 1 min each, and completely passive bins  were excluded from the RMS calculations. These thresholds were determined based on visual inspection, blinded for risk group and outcome data. The data was recoded with a sample rate of 32 Hz.Mullen Scales of Early Learning  is a standardized measure of development for children from birth to 68 months of age in the domains of fine and gross motor skills, visual reception, expressive and receptive language. The Early Learning Composite (ELC) is a standard score  for overall cognitive ability, which was used in the current study for participant characteristics.r = 0.55, p = 0.001 for the ADHD-scales; r = 0.43, p = 0.008 for the PDP-scales) and in all of the following analyses a composite score for the symptom scales calculated as a mean score of the symptom scales of CBCL (rated by parents) and C-TRF (rated by teachers) was used.The Child Behavior Checklist (CBCL) 1½–5 and the Caregiver-Teacher Report Form (C-TRF) are similarly constructed to evaluate behavioral, emotional and social function problems . Both scales have good reliability and validity (Achenbach 1991b). In the current study, the CBCL was rated by parents and the C-TRF was rated by teachers and equivalent pre-school staff. Both forms comprise 99 items that are rated on 0 (not true), 1 (somewhat or sometimes true), or 2 (very or often true). In the present study we used the DSM-related scales of Pervasive Developmental Problems (PDP) as a proxy for ASD symptoms, and the Attention deficit/Hyperactivity problem scale as a proxy for ADHD symptoms. The PDP scale is identical to the DSM ASD-scale in the recent CBCL 1½–5 C-TRF version  apart for the item “afraid of trying new things” that is not included in the recent version. The ADHD scale is identical in both versions. In this study we used a multiple-informant approach by aggregating continuous outcome measures of ASD and ADHD symptoms based on parent- and teacher-ratings. Although disaggregated data may produce more specific report from different informants, in this study we chose to aggregate data in order to present a comprehensive measure of behaviors across setting and to reduce the number of analyses and the risk of type I errors . This alpha-level was considered a reasonable correction without excessively increasing the risk of inflated type II errors. If participants have skipped an item on any of the rating-scales, they will be prompted to fill in that/those items before finishing the questionnaire. This reduces the amount of missing data. However, due to failure of parents and/or teachers to submit ratings on the ECBQ and/or CBCL, 14 children had missing data on these variables, however, for the temperament scales impulsivity, positive anticipation, and sociability 16, 18 and 15 children had missing data, respectively. Due to internal omission, 28 children had missing data on the exuberance measure from the bubble-task, and 23 children had missing data on the accelerometer activity measure. Therefore, total n for the bivariate analyses varied between 42 and 54.Data were converted to z-scores and screened for outliers (z > 3 SD). Six extreme univariate outliers were detected, one on the temperamental scale attentional shifting, one on the cuddliness scale, one on the discomfort scale, one on the soothability scale, and two on the CBCL scale Pervasive Developmental Problems (ASD symptoms). These outliers were replaced with the value next most extreme for each measure . Analysis for normality showed that the collapsed symptom scales of ASD and ADHD (representing averaged parent- and teacher-ratings from the CBCL and C-TRF) and the parent-rated temperament scales of discomfort, frustration, low-intensity pleasure, repetitive motor activity/fidgeting, sociability and soothability were positively skewed. To correct for this non-normal distribution bootstrapped statistical tests were used in the analysis involving these variables  = 0.34, p = 0.04, parent-rated activity level, r(41) = 0.34, p = 0.02, indicating construct validity in the rated activity variables. Increased accelerometer activity level was also related to decreased parent-rated attentional focus, r(42) = 0.32, p = 0.03. Exuberant children in the bubble-task showed less fear as rated by the parent, r(42) = 0.29, p = 0.04. No other correlations were significant between the predictors  at 18 months. At 36 months, symptoms of ASD and ADHD were positively correlated, r(51) = 0.55, p < 001.Descriptive statistics for participant characteristics are presented in Table r(52) = − 0.49, p = 0.001, and this relation remained when partialling out the effect of ASD symptoms, r(51) = − 0.49, p = 0.001. Increased attentional shifting was related to decreased symptoms of ASD, r(52) = − 0.39, p = 0.001 and survived control for symptom overlap, r(51) = − 0.31, p = 0.01.Longitudinal relations between the multi-measured temperament predictors at 18 months and ASD and ADHD symptoms at 36 months are presented in Table r(52) = 0.42, p = 0.002, and this relation survived control for ADHD symptoms, r(51) = 0.43, p = 0.001. Increased infant soothability related to decreased ASD, r(52) = − 0.33, p = 0.01, and ADHD symptoms, r(52) = − 0.36, p = 0.008, but these relations did not hold after controlling for the overlap of respective symptom domain. The bivariate relations between fear and symptoms of ASD and ADHD were not significant, but after control for symptom overlap the relations became significant albeit in the opposite direction for the two symptom domains, that is increased fear was related to increased ASD symptoms, r(52) = 0.33, p = 0.01, and decreased ADHD symptoms, r(52) = − 0.33, p = 0.01.In terms of the behaviors constituting the negative affectivity factor, increased discomfort was related to increased symptoms of ASD, r(48) = − 0.35, p = 0.01. Further, increased parent-rated activity level was related to increased ASD, r(49) = 0.38, p = 0.007, and ADHD symptoms, r(49) = 0.53, p = 0.001, but only the relation to ADHD survived control for symptom overlap, r(48) = 0.42, p = 0.003. Finally, increased sociability was related to decreased ASD symptoms, r(49) = − 0.47, p = 0.001, and this relation remained when controlling for ADHD symptoms, r(48) = − 0.43, p = 0.002.Several behaviors belonging to the surgency factor were related to both ASD and ADHD symptoms. First, the bivariate relations between impulsivity and ASD and ADHD symptoms were not significant, but when controlling for symptom overlap, the relation between increased impulsivity and decreased ASD symptoms became significant, r(42) = 0.38, p = 0.01, but this relation disappeared when controlling for ASD symptoms.In terms of observed exuberant behaviors in the bubble task, neither exuberance nor observed activity level were significantly related to ASD or ADHD behaviors. Activity level as measured by the accelerometer was related to increased ADHD symptoms, either later ASD or ADHD symptoms. These findings suggest that particular early temperamental behaviors may differentiate between early emerging ASD and ADHD symptoms.It is still unclear whether ASD and ADHD characterize different manifestations of the same overarching disorder or if co-occurring ASD and ADHD represent different clinical disorders with distinct etiology and developmental trajectory . Activity level is suggested to predict later ADHD symptoms already from infancy to school-age, and up to adolescence both dimensionally and categorically  vs state (a temporary condition) qualities in the child. The observational measure was primarily used to assess one aspect of temperament, namely exuberance. Indeed, it might be that other types of tasks could elicit more exuberant behaviors and a future direction would be to use a variety of measures to assess this temperamental trait. Moreover, we studied physical activity using a triaxial accelerometer for movement registration. Although this method has been used to assess movement patterns in various contexts  are extensive, and thus it is not unlikely that some of the results generalize to other groups (e.g. primarily at elevated likelihood for ADHD) or to the population more broadly. This is an important avenue for future research. Another point of concern is that our sample is slightly skewed towards high socioeconomic status (SES) which suggests that the families in our study generally experience less economic burden in contrast to low SES families. There is an association between socioeconomic disadvantage and higher prevalence of ADHD . Some of the expected associations, such as the observed exuberance and activity level, were not significant at this threshold and did not clearly show a specific pattern to either ASD or ADHD-symptomatology. More well-powered studies need to further disentangle this question. By using a multi-informant approach (combined parent- and teacher-ratings) we were able to include two perspectives of the symptom level, however a way forward would be to also include clinical estimates of symptoms and finally diagnostic outcome.